NHMRC Research Achievements - SUMMARY
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Austin Hospital Medical Research Foundation
Austin Research Institute
Australian National University
Australian Stem Cell Centre Ltd
Baker IDI Heart and Diabetes Institute
Cancer Council Queensland
Cancer Council Victoria
Children's Medical Research Institute
CSIRO Division of Human Nutrition
Curtin University of Technology
Deakin University
Edith Cowan University
Flinders University
Garvan Institute of Medical Research
Griffith University
Howard Florey Institute
Institute of Medical and Veterinary Science
James Cook University
La Trobe University
Ludwig Institute for Cancer Research
Macfarlane Burnet Institute for Medical Research and Public Health
Macquarie University
Mater Medical Research Institute, Brisbane
Melbourne Health
Menzies Research Institute
Menzies School of Health Research
Monash University
Murdoch Childrens Research Institute
NSW Cancer Council
Peter MacCallum Cancer Centre
Prince Charles Hospital
Prince Henry's Institute of Medical Research
Princess Alexandra Hospital
Queensland Institute of Medical Research
Queensland University of Technology
RMIT University
Royal Adelaide Hospital
Royal Prince Alfred Hospital
NHMRC Research Achievements - SUMMARY
St Vincent's Institute of Medical Research
Swinburne University of Technology
Sydney West Area Health Service
The Children's Hospital at Westmead
University of Adelaide
University of Canberra
University of Melbourne
University of New England
University of New South Wales
University of Newcastle
University of Queensland
University of South Australia
University of Sydney
University of Tasmania
University of Western Australia
University of Western Sydney
University of Wollongong
Victor Chang Cardiac Research Institute
Victoria University
Walter and Eliza Hall Institute
NHMRC Research Achievements - SUMMARY
Grant ID: 469002
Start Year: 2008
CIA Name: Dr Uwe Ackermann
End Year: 2011
Admin Inst: Austin Hospital Medical Research Foundation Grant Type: NHMRC Project Grants
Main RFCD: Radiotherapy and Nuclear Medicine
Total funding: $727,856
Title of research award:
Novel tools for the imaging of tumor hypoxia using PETNovel tools for the imaging of tumor hypoxia using
PET
Lay Description (from application):
Fast growing tumors often outgrow the ability of blood vessels to properly supply them with nutrients and
oxygen. This creates tissue areas within the tumor that are lacking oxygen and are highly resistant to
radiotherapy and chemotherapy. Imaging these areas using nuclear medicine techniques has now become
important for therapy planning of cancer sufferers. This project aims to improve the properties of the existing
agents in order to better select patients for a particular type of treatment.
Research achievements (from final report):
Not Available
Expected future outcomes:
N/A
Name of contact:
Uwe Ackermann
Email/Phone no. of contact:
ackerman@petnm.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 223310
Start Year: 2003
CIA Name: Prof Vasso Apostolopoulos
End Year: 2005
Admin Inst: Austin Research Institute
Grant Type: NHMRC Project Grants
Main RFCD: Immunology not elsewhere classified
Total funding: $489,750
Title of research award:
Crystallographic studies of non-canonical peptides binding to MHC Class I molecules.Crystallographic studies
of non-canonical peptides binding to MHC Class I molecules.
Lay Description (from application):
Virus infected cells and cancer cells are recognised and eliminated from our body by specialised cells called Tcell lymphocytes. This recognition process is the key step in the immune response and some fundamental
questions in immunology are centred on the nature of this process. At the molecular level, the recognition is
mediated by the specific interaction between proteins on the surface of the cells. On the T-cell lymphocyte, the
T-cell receptor (TCR) binds specifically to a protein called the MHC on the surface of the target cell. The target
cell can be a cancer cell, or an infected antigen presenting cell (specialised cells in the body which present
protein fragments (peptides) on their surface via MHC). The structure of a TCR and TCR/MHC have been
"solved" in terms of the shape of the molecules at atomic resolution, bringing detailed information on how
these two proteins interact with each other. In this proposal the structural basis of antigen presentation and
recognition in cell-mediated immunity will be determined by three-dimensional structures of different peptides
on MHC by x-ray crystallography. Cell surface antigen presentation by MHC molecules is crucial for initiating
the cellular immune response against invading pathogens and cancer. This proposal encompasses a combined
biochemical, immunological, and biophysical approach to understand the range of ligands which can bind to
MHC which are subsequently recognised by the TCR. To understand the antigenic properties of modified
peptides at the structure level, the x-ray structure of MHC with modified bound synthetic peptides will be
determined.
Research achievements (from final report):
On the T-cell lymphocyte, the T-cell receptor (TCR) binds specifically to a protein called the MHC on the
surface of the target cell. The target cell can be a cancer cell, or an infected antigen presenting cell (specialised
cells in the body which present protein fragments (peptides) on their surface via MHC). The structure of a TCR
and TCR/MHC have been "solved" in terms of the shape of the molecules at atomic resolution, bringing
detailed information on how these two proteins interact with each other. To date, peptides which bind to MHC
have been defined to contain certain amino acids at certain positions to enable binding of the peptide to MHC these peptides are called 'canonical peptides'. We have identified a number of peptides which do not contain the
canonical amino acids ie. non-canonical. We determined structurally and immunologically a number of noncanonical peptides, short-5-mers, long-14 and 18-mers, a glycopeptide, a low affinity peptide and made
mutations to peptides to increase the affinity of low affinity binding peptides. This information will broaden
our knowledge and understanding of how peptides bind to MHC class I molecules and will aid in improved
peptide-based cancer vaccines.
Expected future outcomes:
This information will broaden our knowledge and understanding of how peptides bind to MHC class I
molecules and will aid in improved peptide-based cancer vaccines.
Name of contact:
Vasso Apostolopoulos
Email/Phone no. of contact:
vasso@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 148927
Start Year: 2001
CIA Name: Dr Paul Waring
End Year: 2003
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $256,528
Title of research award:
Mechanisms Underlying the Biochemical Activity of Scabrosin Esters and other Epipolythiodioxopiperazine
Toxins.Mechanisms Underlying the Biochemical Activity of Scabrosin Esters and other
Epipolythiodioxopiperazine Toxins.
Lay Description (from application):
Fungi produce a variety of chemicals which are toxic to animals. The fungi have probably developed the ability
to synthesize and secrete these toxins as part of a chemical defence mechanism and/or in order to limit other
microbial life forms because of nutrient competition. Some of these toxins will selectively kill microbes such
as bacteria and other fungi as well as simpler life forms such as viruses, which can cause pathological changes
to human beings. Fungal toxins may also be useful for control of proliferative diseases such as cancer. Because
fungi have had many millions of years to select for the most efficient toxins, they have been a valuable source
of potent toxins for study. Some of these toxins are now in use clinically to treat human diseases ie penicillin
and cyclosporin A. A fundamental understanding of fungal toxins is important to ensure the availability of new
drugs to combat resistant strains of bacteria and to provide clues for the synthesis of new drugs to treat cancer
which can also develop resistance to currently used drugs.
Research achievements (from final report):
This research led to a better understanding of the mode of action of a class of fungal toxins. We discovered a
new mechanism by which these toxins are concentrated in cells.
Expected future outcomes:
The mechanism discovered may enable design of new drugs to treat cancers resistance to currently available
drugs.
Name of contact:
Paul Waring
Email/Phone no. of contact:
Paul.Waring@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 179811
Start Year: 2002
CIA Name: Prof Frances Shannon
End Year: 2004
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $452,310
Title of research award:
A functional proteomics approach to the study of inducible gene transcription in a chromatin context.A
functional proteomics approach to the study of inducible gene transcription in a chromatin context.
Lay Description (from application):
Cells of the immune system detect assaults on the body such as infection, inflammatory or allergy-causing
agents. Using a complex set of signaling pathways, the cells translate this information into a change in the
pattern of expressed genes in those cells. These changes in gene expression occur rapidly and are generally
transient. The changes that occur in gene expression pattern leads to functional changes in the cell that in turn
are critical for the downstream events of the immune response. One set of genes that is rapidly and transiently
switched on in response to immune stimuli in T cells (one important immune cell type) are those that encode
proteins known as cytokines. These cytokines function to send messages between cells thus activating
downstream events of the immune response. Thus understanding the mechanism of how these genes are
switched on and off is critical in understanding an immune response and in developing potential novel
therapeutics based on gene transcription. Genes exist in the nucleus of the cell in the context of a complex
structure known as chromatin. The process of RNA transcription from these genes, therefore, takes place in the
context of this complex structure. While there have been many studies defining the molecular mechanisms that
control the expression of cytokine genes, little attention has been paid to the role of chromatin in the inducible
and transient nature of this gene transcription. This proposal addresses the molecular mechanisms by which
inducible cytokine gene transcription occurs in a chromatin context. We will use both in vitro and in vivo
approaches to probe the structure of chromatin that overlies these genes and the mechanism by which this
structure is altered to allow the genes to be expressed.
Research achievements (from final report):
Activation of T cells by foreign antigens is one of the key events in an immune response. When T cells are
activated they produce a variety of cytokines that communicate with other cell types in the immune syatem or
act in an autocrine fashion to drive proliferation and differentiation of the T cells. Upon initial activation,
cytokines such as GM-CSF (a myeloid growth factor) and IL-2 (a T cell growth factor) are made in large
quantities. The mechanisms by which these genes are activated to express mRNA and hence protein is of great
interest in understanding how the immune syatem responds to foreigh or self antigens. , One important aspect
of gene activation is the changes that occur in the packaging of the DNA around the inducibal genes. In this
project we have shown that chromatin is remodelled across a very small promoter region, in the order of one
nucleosomes worth of DNA and that this remodelling involves the loss of histone proteins from this region. We
have charaterized the signaling needs for this histone loss and shown a specific need for the NF-kB but not the
NFAT familiy of transcription factors. In addition, we showed that the SWI/SNF chromatin remodelling
complexes may play an important role in the chromatin structure across these gene promoters. We have also
investigated the relationship between the SWI/SNF complexes and the NF-kB family of transcription factors.
Expected future outcomes:
Work from this project has underpinned further recent work on models of chromatin remodelling in T cells
which match models being proposed from yeast systems. Thus this work will lead to a better understanding of
gene transcription in eukaryotes in general.
Name of contact:
Prof Frances Shannon
Email/Phone no. of contact:
frances.shannon@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 179818
Start Year: 2002
CIA Name: Prof Philip Board
End Year: 2004
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $481,980
Title of research award:
The role of Zeta and Omega class glutathione transferases in endobitic and xenobiotc metabolismThe role of
Zeta and Omega class glutathione transferases in endobitic and xenobiotc metabolism
Lay Description (from application):
The glutathione transferases are enzymes that play a significant role in the protection of cells from harmful
chemicals in the environment. While some of the chemicals that are detoxified by glutathione transferases
cause cancer, and other diseases, these enzymes also eliminate some of the drugs that are used in
chemotherapy. Variations in the type and amount of glutathione transferase in a cell can make a normal cell
susceptible to cancer causing chemicals and make a cancer cell resistant to anti cancer drugs. We have
discovered two new forms of glutathione transferase called Zeta and Omega. The new research to be
undertaken here is aimed at understanding the role of these new enzymes in protection against foreign
chemicals and the role these enzymes play in normal cellular metabolism. Because the Zeta class glutathione
transferase is part of a pathway designed to eliminate excessive amounts of the amino acid tyrosine, we will
determine if its inhibition will provide a new treatment for patients with a disease called hereditary
tyrosinemia. We will also study the genetic and environmental factors that determine the amount of Zeta and
Omega glutathione transferase produced in cells
Research achievements (from final report):
Glutathione transferase Zeta (GSTZ) catalyses an important step in the metabolism of tyrosine and
phenylalanine as well as the metabolism of potentially carcinogenic alpha halo acids that can contaminate
chlorinated drinking water. Mutations were made in residues that contribute to the active site of GSTZ1-1. , ,
The mutant enzymes were characterised with aleylacetoaceone and chlorofluroactetate as model substrates. In
addition 2-bromo-3-(4nitrophenyl)propionic acid was synthesized and tested as a novel substrate for
spectrophotometric assays of GSTZ activity. These studies provided a greated understanding of the enzyme's
reaction mechanism., , A GSTZ knockout mouse was generated to study the importance of GSTZ in the
metabolism of tyrosine and phenylalanine. The mouse shows significant pathology when exposed to high
dietary phenylalanine. The knockout mice are also sensitive to low doses or paracetamol. This toxicity may be
a problem in humans with CGTZ 1-1 deficiency., , Two Omega class glutathione transferase genes were
identified and several polymorphisms have been characterized. One novel variant of GST01 results in the
deletion of glutamate155. The resulting enzyme has slightly elevated activity but has decreased heat stability.
We noted that the GSTO genes mapped to a chromosomal region (10Q24.3) that has been implicated in the
age-at-on set of Alzheimer's and Parkinson's diseases. We proposed that a GSTO gene may be the predicted
age-at-onset gene but a study of 350 Parkinson's patients was negative. However, two recent reports from other
laboratories found significant linkage between GSTO genes and age-at-onset of Alzheimer's disease.
Expected future outcomes:
Our results with GSTZ deficient mice suggest that patients receiving dichloroacetic acid to treat chronic lactic
acidosis may be very sensitive to paracetamol toxicity., , Genetic polymorphisms that modulate the expression
or function of Omega class glutathione transferases may influence age-at-onset of Alzheimer's disease.
Name of contact:
Philip Board
Email/Phone no. of contact:
Philip.Board@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 179823
Start Year: 2002
CIA Name: Prof David Tremethick
End Year: 2004
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $436,980
Title of research award:
The function of an essential histone variant during early development.The function of an essential histone
variant during early development.
Lay Description (from application):
Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus, DNA is not in a free
form but is covered with an equivalent weight of protein to form a structure known as chromatin. Chromatin is
a periodic structure made up of repeating, regularly spaced subunits, the subunit being the nucleosome. A
nucleosome consists of a group of proteins (histones) wrapped around with DNA. A nucleosome is capable of
blocking gene expression therefore one important function of chromatin is to prevent unwanted gene
expression which is essential to allow an organism to develop properly. When gene expression is not
accurately controlled by chromatin developmental defects or cancer could result from the production of
incorrect proteins.
To control correct gene expression, highly specific mechanisms must operate in the cell
to remove, or disrupt, nucleosomes at certain genes at a precise time during development. One mechanism that
we believe to be important is changing the make-up of a nucleosome. This can be achieved in the cell by the
replacement of histones with different specialised forms of these histones (variants). It is thought that these
histone variants could specifically expose certain genes and thereby turn them on. Once the correct protein is
made in sufficient amounts the histone variants could be rapidly exchanged for the normal histones to shut off
the gene. Employing a new approach, we will study one of these histone variants to discover the role it plays in
turning genes on at precise times in early development during the formation of different specialised cell types.
This new information may define targets for the prevention of incorrect gene expression during cancer
progression or abnormal development.
Research achievements (from final report):
Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus, DNA is not in a free
form but is covered with an equivalent weight of protein to form a structure known as chromatin. Chromatin is
a periodic structure made up of repeating, regularly spaced subunits, the subunit being the nucleosome. A
nucleosome consists of a group of proteins (histones) wrapped around with DNA. A nucleosome is capably of
blocking gene expression therefore one important function of chromatin is to prevent unwanted gene
expression which is essential to allow an organism to develop properly. When gene expression is not accurately
controlled by chromatin developmental defects or cancer could result from the production of incorrect
proteins.,
To allow gene expression, highly
specific mechanisms must operate in the cell to remove, or disrupt, nucleosomes at certain genes at a precise
time during development. On the other hand, to prevent gene expression, chromatin is further stabilised. This
project has uncovered an important mechanism regulating early development in which the 'make-up' of a
nucleosome is altered by replacement of histones with different specialised forms of these histones (variants).
Specifically, we demonstrated that the histone variant H2A.Z has a specific role during early metazoan
development by forming large compacted chromosomal domains required for gene repression. Most
importantly, we identified the molecular determinants of H2A.Z that enables this variant to perform it essential
developmental role. This new information may define targets for the prevention of incorrect gene expression
during cancer progression or abnormal development.
,
Expected future outcomes:
A greater understanding of how a fertilized mammalian egg cell can differentiate into a multicellular organism.
This will have important implications with regards to understanding normal and abnormal cellular processes.
Name of contact:
David Tremethick
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
david.tremethick@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 179842
Start Year: 2002
CIA Name: Dr Anneke Blackburn
End Year: 2005
Admin Inst: Australian National University
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Toxicology (incl. Clinical Toxicology)
Total funding: $254,533
Title of research award:
Title of tyrosine catabolism genes and accumulation of assoc metabolites in mouse mammary epitheliumpotential low penetTitle of tyrosine catabolism genes and accumulation of assoc metabolites in mouse
mammary epithelium-potential low penet
Lay Description (from application):
Not Available
Research achievements (from final report):
Several genetic factors potentially involved in breast cancer risk were investigated through a mouse model of
breast cancer. While one factor was determined unlikely to be a significant contributor, two other genetic
regions show greater promise. These regions were defined and collaborations established to investigate the
corresponding regions and genes in human population studies on breast cancer patients.
Expected future outcomes:
Further investigations into the genes involved in these susceptibility loci will contribute to our understanding of
breast cancer development, and what genetic factors may put women at risk of developing breast cancer,
potentially leading to better screening of women.
Name of contact:
Anneke Blackburn
Email/Phone no. of contact:
Anneke.Blackburn@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 224226
Start Year: 2003
CIA Name: Prof David Tremethick
End Year: 2005
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $267,750
Title of research award:
Mechanisms by which chromatin modulates gene expression.Mechanisms by which chromatin modulates gene
expression.
Lay Description (from application):
Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus, DNA is not in a free
form but is covered with an equivalent weight of protein to form a structure known as chromatin. Chromatin is
a periodic structure made up of repeating, regularly spaced subunits, the subunit being the nucleosome. A
nucleosome consists of a group of proteins (histones) wrapped around with DNA. A nucleosome is both
capable of blocking and activating gene expression. Therefore one important function of chromatin is to tightly
regulate gene expression which is essential to allow an organism to develop properly. When gene expression is
not accurately controlled by chromatin developmental defects or cancer can result from the production of
incorrect proteins.
To control correct gene expression, highly specific mechanisms must operate in the cell
to remove, or modify, nucleosomes at certain genes at a precise time during development. One mechanism that
we believe to be important is changing the make-up of a nucleosome. This can be achieved in the cell by the
replacement of histones with different specialized forms of these histones (variants). We believe that these
histone variants can specifically generate chromosomal domains which could in some cases expose or in other
cases hide certain genes and thereby turn them on or off. Employing a new approach, we will study one of
these histone variants to discover the role it plays in determining the type of chromosomal domain made and
the role of this domain has in turning genes on or off at precise times in early development during the
formation of different specialized cell types. This new information may define targets for the prevention of
incorrect gene expression during cancer progression or abnormal development.
Research achievements (from final report):
Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus, DNA is not in a free
form but is covered with an equivalent weight of protein to form a structure known as chromatin. Chromatin is
a periodic structure made up of repeating, regularly spaced subunits, the subunit being the nucleosome. A
nucleosome consists of a group of proteins (histones) wrapped around with DNA. A nucleosome is both
capable of blocking and activating gene expression. Therefore one important function of chromatin is to tightly
regulate gene expression which is essential to allow an organism to develop properly. When gene expression is
not accurately controlled by chromatin developmental defects or cancer can result from the production of
incorrect proteins.To control correct gene expression, highly specific mechanisms must operate in the cell to
remove, or modify, nucleosomes at certain genes at a precise time during development. One mechanism that
we believe to be important is changing the 'make-up' of a nucleosome. This can be achieved in the cell by the
replacement of histones with different specialized forms of these histones (variants). In this study we have
shown that these histone variants can specifically generate chromosomal domains which can hide certain genes
and thereby turn them off. Employing a new approach, we have discovered the role of histone variants in
assembling a compact repressive chromatin domain that has the potential to turns genes off at precise times
during early development when specialized cell types are formed. In addition, we have discovered that this
comapcted domain is essential to maintain chromosomes in a stable state.
Expected future outcomes:
The significance of this study is that in the future, it will help to understand why chromosomes become
unstable in cancer cells, and why genes become mis-regulated during early human development that lead to
developmental abnormalities. This new information may define targets for the prevention of incorrect gene
expression during cancer progression or abnormal development.
Name of contact:
NHMRC Research Achievements - SUMMARY
David John Tremethick
Email/Phone no. of contact:
david.tremethick@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 224274
CIA Name: Dr Alison Shield
Admin Inst: Australian National University
Main RFCD: Basic Pharmacology
Total funding: $285,200
Start Year: 2004
End Year: 2008
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Functional genomic studies of the human glutathione-S-transferase omega (GSTO) familyFunctional genomic
studies of the human glutathione-S-transferase omega (GSTO) family
Lay Description (from application):
Not Available
Research achievements (from final report):
We studied the function of two new members of the glutathione transferase (GST) family, GSTK1 and
GDAP1. , GSTK1 represents a novel family of glutathione conjugating enzymes with an undefined function. In
a GSTK1 knockout mouse strain we unexpectedly found that the male mice are predisposed to changes in
kidney pathology. We also demonstrated that they are sensitive to paracetamol-induced liver toxicity. We hope
this will help us to understand the mechanisms of paracetamol toxicity., GDAP1 mutations have been
genetically linked to peripheral neuropathy but how this protein contributes towards the disease is not
understood. The protein GDAP1 is similar in structure to GSTs but we have demonstrated that it does not have
typical glutathione conjugating activity. It is widely expressed in the human body and appears to be important
in the control of mitochondrial networks. This is helping us to understand how changes in the mitochondrial
network contributes to peripheral neuropathies., We also studied the regulation of GSTK1 and GSTO1. We
have identified key transcription sites responsible for regulating these gene plus common genetic
polymorphisms that cause changes in their regulation. This knowledge will be used to help us understand how
genetic changes in these genes can lead to increased susceptibility to disease. , The studies undertaken will
ultimately help us to understand the biology underlying some common human disease, such as kidney disease
and peripheral neuropathies, which may help us to design better therapies to treat these diseases.
Expected future outcomes:
We will be able to identify the endogenous functions for GSTK1 and GDAP1, which we hope help us to
understand the pathophysiology of glomerular nephropathy and peripheral neuropathy, respectively.
Name of contact:
Alison Shield
Email/Phone no. of contact:
Alison.Shield@canberra.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268058
CIA Name: Prof Francis Bowden
Admin Inst: Australian National University
Main RFCD: Venereology
Total funding: $350,500
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Screening for Chlamydia trachomatis with routine Pap smears in general practice: A randomised controlled
trialScreening for Chlamydia trachomatis with routine Pap smears in general practice: A randomised controlled
trial
Lay Description (from application):
Genital chlamydia infection is the most commonly reported infectious disease in Australia. Notifications have
increased three fold since 1995; five-fold in the ACT and surveillance data underestimate the true incidence of
the disease in the community. Chlamydia is associated with immediate morbidity in men and women including
urethritis, epididymo-orchitis, cervicitis, and pelvic pain and long-term complications including pelvic
inflammatory disease, ectopic pregnancy and tubal factor infertility. The economic costs of Chlamydial
infection in Australia have been estimated to be as high as $160 million each year. In the ACT 73.8% of
chlamydial infections occur in the 20-40 year old group. Between 60 and 70% of women in this age range
participate in Pap screening every two years. While targeted screening for Chlamydia in women is effective in
the US, there are few studies that investigate its value in an Australian setting. In this randomised controlled
clinical trial we aim to test the novel hypothesis that the routine offer of chlamydia testing to women between
20 and 40 years who undergo Pap screening significantly increases the detection of Chlamydia in that
population. This is the first randomised-controlled trial of its type and is an extension of a current nonrandomised pilot study of linked Chlamydia-Pap screening in the primary care setting. The aim is to determine
if the program can be incorporated more widely in the ACT. The study will: Measure the impact of linked
chlamydia-Pap screening on chlamydia screening participation rates More accurately determine the
epidemiology of genital chlamydial infection in this age group and social setting; Undertake an economic
evaluation of this approach; Determine if promoting the Pap smear as an opportunity for chlamydial screening
increases the uptake of Pap screening in younger women Aid in the development of a National Chlamydia
Screening strategy
Research achievements (from final report):
Combining chlamydia screening with the Pap smear increases the proportion of women screened for chlamydia
in general practice. Our results show that the approach used for the control group (asking general practitioners
to implement targeted screening guidelines) was less effective in increasing screening rates than simply asking
doctors in the intervention group to perform combined testing without any assessment of risk. The prevalence
of chlamydia in the tested sample was 4.0%, with no statistically significant difference between the rates for
intervention and control groups, which highlights the difficulty in identifying who is at greater risk of infection.
There was no statistically significant difference between the overall rates of infection detected in the 16-25 year
old group and the 25-30 year old group (5.7% and 4.6% respectively), demonstrating the value of screening
women up to the age of 30. Combined chlamydia/Pap testing does not exclude men if proper contact tracing of
the sexual partners of chlamydia positive women is instituted as part of the program. Widespread
implementation of this approach would represent an important public health innovation that would require little
additional infrastructure support in settings where there is cervical screening. Although a vaccine against
human papillomavirus is now available, it is likely that the current guidelines for Pap screening in Australia
will continue for at least the next ten years, securing the value of the combined testing strategy for the near
future at least.
Expected future outcomes:
Combined chlamydia and Pap testing will become commonplace in the general practice and other settings.
Widespread adoption of this approach will help to reduce the prevalence of chlamydia infection in both women
and men, limit the occurrence of complications such as infertility and chronic pelvic pain and save money.
NHMRC Research Achievements - SUMMARY
Name of contact:
Professor Francis J. Bowden
Email/Phone no. of contact:
frank.bowden@act.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268084
CIA Name: Prof Christopher Goodnow
Admin Inst: Australian National University
Main RFCD: Genetics not elsewhere classified
Total funding: $2,281,300
Start Year: 2004
End Year: 2011
Grant Type: NHMRC Enabling Grants
Title of research award:
Australian Phenome BankAustralian Phenome Bank
Lay Description (from application):
The Australian Phenome Bank will establish a frozen sperm bank, database, and training program to enable
access by the research community to new strains of genetically modified mice. Efficient access to diverse
strains, provided by the Phenome Bank, will be critical for translating the human genome sequence into an
understanding of specific mechanisms regulating all the body organ systems in health and disease, and for
developing new disease prevention and treatment approaches.
Research achievements (from final report):
The use of genetically modified mouse strains is vital for medical research advances. Generationa and
maintenance of these strains is expensive. It is therefore important to have systems in place to protect these
strains from disaster and loss and to inform researchers whether a strain of interest already exists in Australia.
The main aims of the Australian Phenome Bank (APB) were to provide a cryopreservatin service, thereby
archiving and protecting the genetic material of these strains and to establish a database of the strains in
Australia so that researchers could determine if they needed to invest resources into creating or importing a
strain or whether it already exists in Australia. To this end over the period of the Enabling Grant awarded to
establish the Australian Phenome Bank 2,976 strains have been listed on the database and 1,472 strains were
cryopreserved. In addition, housing mouse strains not immediately required for current experimental work is
expensive. Cryopreservation of the strains allows the live colonies to be removed but preserve them for use in
the future, and to minimize genetic drift.
Expected future outcomes:
The Australian Phenome Bank is critical infrastructure for the medical research industry. In the near future it is
envisaged all strains will be listed on the database and all strains will be cryopreserved. In addition, the
Australian Phenome Bank will provide Australian researchers with enhanced links to similar International
respositories, further expediting access to strains held elsewhere..
Name of contact:
Dr Stuart Read
Email/Phone no. of contact:
stuart.read@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 316917
CIA Name: Prof Frances Shannon
Admin Inst: Australian National University
Main RFCD: Gene Expression
Total funding: $534,000
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
The role of NF-kB transcription factors in regulating T cell transcription networksThe role of NF-kB
transcription factors in regulating T cell transcription networks
Lay Description (from application):
T cells are a key element of the adaptive immune response and help to distinguish between self and non-self.
Hence, an inappropriate T cell response can lead to autoimmunity and chronic inflammatory disease. When T
cells are activated by an immune signal they switch on the production of an array of proteins that control both
T cell function and other arms of the immune system. The genes encoding these proteins possess molecular
switches (promoters and enhancers) that respond to immune signals. These molecular switches bind groups of
proteins known as transcription factors. One family of transcription factors that plays a key role in T cell
function is the NF-kB family consisting of five different members, three of which are important in T cell
function. Aberrant NF-kB function or expression has been associated with autoimmunity, chronic inflammation
and cancer. In addition, NF-kB proteins are key components of transplant rejection. There is enormous interest
in using the NF-kB pathway as a therapeutic target for these pathologies. We currently have a detailed
knowledge of the biology of these factors through studies of mice lacking specific family members. While we
know some of the genes that are switched on by the NF-kB proteins, we currently lack a sufficiently detailed
knowledge of NF-kB-regulated genes in order to link the molecular function with the biological outcomes. In
order to understand the molecular mechanism of NF-kB function and relate this to the biological outcomes, we
need a global view of NF-kB action in the cell. This proposal uses both experimental and computational
approaches to decipher the gene expression program controlled by NF-kB proteins in T cells. The T cell
transcription networks in which NF-kB proteins participate will also be investigated. The knowledge generated
by these experiments will provide a solid basis for designing therapeutic approaches based on the NF-kB
pathway.
Research achievements (from final report):
This grant provided us with the resources to begin examining the role of the various members of the NF-kB
family in the regulation of gene expression in T cells. The novel aspects of the work were combined use of
both experimantal and computational approaches to define the gene sets regulated by these important preinflammatory transcription factors. Methods for genome-wide expression profiling were developed and
computational methods for transcription factors binding site analysis were introduced to the research profile of
the lab and the institute. Target genes for several of the NF-kB factors were identified leading to several
publications. A potentail role for one of these factors in controling regulatory T cells and hence autoimmune
disease was identified and this became the subject of further research and successful funding.
Expected future outcomes:
The introduction of these methodologies has lead to genome-wide approaches being applied to the function of
other important transcription factors in the immune system, eg the reglatory T cell factor, Foxp3.
Name of contact:
Prof Frances Shannon
Email/Phone no. of contact:
frances.shannon@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 316927
Start Year: 2005
CIA Name: Prof David Tremethick
End Year: 2007
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $504,000
Title of research award:
The role of heterochromatin in regulating cellular proliferation and developmentThe role of heterochromatin in
regulating cellular proliferation and development
Lay Description (from application):
Fundamental to the development of a multicellular organism is that for each cell type performing a specialised
function, a different set of genes are turned on with the remainder being shut off. One of the most significant
unanswered questions in biology is how a cell-type specific gene expression profile is established during early
development. The answer to this question has important implications in understanding normal and abnormal
cellular processes. Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus,
DNA is not in a free form but is covered with an equivalent weight of protein (histones) to form a structure
known as chromatin. It has become clear that the chromatin structure encompassing a gene is the critical factor
that determines whether a gene is expressed or silenced. We propose that developmental and cell-type specific
mechanisms operate in a cell to assemble genes into highly specialised chromatin structures that permit
(euchromatin) or restrict (heterochromatin) gene expression. In other words, the genome of each different cell
type is organised into a unique and dynamic "chromatin pattern" and this pattern determines the gene
expression profile. This investigation will show that the critical cellular mechanism that determines the
chromatin pattern for a particular cell type is the regulation of the quantity and quality of heterochromatin.
Specifically, we will demonstrate that this is achieved, in a developmental and tissue specific manner, by
changing the make-up of chromosomal domains through the replacement of histone proteins with specialised
forms of histones called variants . In addition, we will expose a new mechanism of how heterochromatin
formation controls the rate of cellular proliferation. This information will provide new insights into how gene
expression profiles are established at precise times in early development, and offer a new strategy to inhibit the
proliferation of cancer cells.
Research achievements (from final report):
A fundamental unanswered question in biology is how, at the molecular level, different cells within a multicellular organism carry out specialized functions, to ultimately produce a unique phenotype, when every
differentiated cell type inherits exactly the same genes. We have discovered that the essential histone variant
H2A.Z is a critical structural and functional epigenetic component of heterochromatin which provided us a
window of opportunity to study how heterochromatin, and its gene silencing role, is established during early
development. We found that gene expression is regulated during early development by major and dynamic
chromatin remodelling events that occur to define different cell lineages. This involves the establishment of a
repressive chromatin state to restrict expression of inappropriate genes. This study also provided new insights
into the alterations required for tumourigenesis by showing that heterochromatin formation plays a crucial role
in all aspects of chromosome behaviour including genome stability and chromosome segregation. This new
information could lead to the development of a new simple diagnostic test for cancer progression, which would
involve the simple immunofluorescence analysis of heterochromatin since the results of this study raises the
possibility that heterochromatin becomes disrupted when cancer cells become metastatic. Finally, we
discovered that H2A.Z regulates cell mobility during development and tissue homeostasis raising the
possibility that new therapeutics can be developed to enhance wound healing and tissue regeneration. , ,
Expected future outcomes:
The ability of H2A.Z to regulate heterochromat formation and cell mobility may produce a framework to target
therapeutics that enhance wound healing and tissue regeneration, and inhibit the spread of cancer.
Name of contact:
David Tremethick
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
david.tremethick@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 316949
CIA Name: Dr JOSEPH ALTIN
Admin Inst: Australian National University
Main RFCD: Tumour Immunology
Total funding: $430,250
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
A NOVEL APPROACH FOR TARGETING DNA TO DENDRITIC CELLS IN VIVO FOR VACCINE
DEVELOPMENT AND CANCER IMMUNOTHERAPYA NOVEL APPROACH FOR TARGETING DNA
TO DENDRITIC CELLS IN VIVO FOR VACCINE DEVELOPMENT AND CANCER
IMMUNOTHERAPY
Lay Description (from application):
The use of genetic material, known as DNA, as a vaccine, has been a relatively new advance in vaccination
technology with potential for combating many infectious diseases and cancers. The use of DNA has the
advantage that it can be easily manipulated to develop new vaccines that have the desired preventative and/or
immunotherapeutic effect. For optimal effect, however, the DNA to be used as a vaccine needs to be targeted
to specific cell types in the body. Evidence suggests that a minor population of cells known as dendritic cells,
which are present in blood and other tissues, play an important role in eliciting the effects of DNA vaccines.
However, current methods for delivering DNA to these cells often lack selectivity in delivery, and/or use
viruses to deliver the DNA. This can pose the risk of allergic type reactions and/or possibly cause tumours.
The use of small membranous vesicles known as liposomes, made of phospholipids, has recently attracted
considerable interest as DNA delivery vehicles, since these are considered safe, and have the potential to
deliver large quantities of DNA. Although DNA can easily be packaged inside liposomes, it is has not been
easy to target the liposomes and their contents (eg. encapsulated DNA) to specific cells (such as dendritic cells)
within the body. We have recently produced a novel chelator lipid molecule which can be used to conveniently
attach onto the liposome surface specific targeting molecules, such as engineered forms of antibody fragments,
that can target or "steer" the liposomes together with their payload (eg. the DNA), directly to dendritic cells.
This project will test the potential for using such targeted liposomes as DNA vaccines by examining whether
liposomes containing DNA for a model antigen can be used in vaccinations to inhibit the growth and metastasis
of a highly metastatic tumour (melanoma) in mice.
Research achievements (from final report):
The ability to deliver genetic material (known as genes or DNA) to specific cells in the body has enormous
potential not only in the treatment of metabolic/genetic disorders in patients, but also for producing vaccines
that can be used to enhance the ability of the body's immune system to combat infectious diseases and cancer.
In this project we developed a novel approach for targeting DNA to specific cells. The relatively large
molecules of plasmid DNA (pDNA) encoding for a reporter gene were condensed and incorporated with
chelator lipid-containing liposomes to form lipid/pDNA structures called lipoplexes. These lipoplexes could be
engrafted with a histidine-tagged targeting molecule and targeted to cells such as dendritic cells (DCs),
specialised antigen-presenting cells crucial for initiating adaptive immune responses, to induce efficient
expression of the reporter gene. Interestingly, we found that liposomes and lipoplexes can also be targeted to
DCs engrafting relatively short histidine-tagged synthetic peptides that have similarity with DC-activating
proteins such as flagellin, a protein involved in bacterial motility and in the body acts as an important trigger
for generating immune reponses against microbial infections. Vaccination of mice with antigen-containing
liposomes or membrane vesicles engrafted with these peptides can target the antigen toDCs, induce potent
immune responses to the targeted antigen, and can potently inhibit tumour growth and metastasis in a mouse
tumour model of metastatic melanoma. Since the peptides also bind to human DCs, our results indicate that this
approach has potential in the development of novel DNA vaccines and immunotherapies for cancer.
Expected future outcomes:
Our approach for delivering genes has applications for the treatment of genetic disorders, and for targeting
DNA to dendritic cells to produce more effective DNA vaccines that can be used to enhance immunity to
NHMRC Research Achievements - SUMMARY
infections and for the immunotherapy of cancer. The approach could potentially circumvent the need to
manipulate a patient's DCs ex vivo for use in cancer immunotherapy.
Name of contact:
Joseph G. Altin
Email/Phone no. of contact:
Joseph.Altin@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 316955
Start Year: 2005
CIA Name: Prof Philip Board
End Year: 2007
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $471,000
Title of research award:
Pharmacogenetic investigations of glutathione transferasesPharmacogenetic investigations of glutathione
transferases
Lay Description (from application):
Members of the family of enzymes known as glutathione transferases are known to be responsible for the
metabolism and detoxification of a wide range of compounds including therapeutic drugs and cancer causing
chemicals. Genetic variation in an individual's compliment of glutathione transferases can alter their response
to drug treatment or their susceptibility to cancer. This study will investigate (1)the genetic mechanisms that
alter the production of glutathione transferases, (2) the characteristics of a new class of glutathione transferases
and (3) the role of glutathione transferase A4 in protecting against disorders such as atherosclerosis and
Parkinson's disease.
Research achievements (from final report):
We discovered a second Omega class glutathione transferase gene (GSTO2). GSTO2-2 catalyses similar
reactions to GSTO1-1 but has exceptionally high dehydroascorbate reductase activity. We identified a N142D
polymorphism but biochemical characterization did not find differences in activity with dehydroascorbate,
monomethylarsonate (V) or dimethylarsonate (V). It is likely that GSTO2-2 is involved in the metabolism of
arsenic trioxide that is used for cancer therapy. , The Studies of the Zeta Class GSTs resulted in the
identification of a range of polymorphisms in the promoter of the human GSTZ1 gene. Some of these SNPs
alter GSTZ1 expression, which may alter the pharmacokinetics of dichloroacetic acid, which is used
therapeutically for the treatment of lactic acidosis and is proposed as a novel cancer therapy. , We also
identified a new member of the glutathione transferase structural family that is identical to ganglioside-induced
differentiation-associated protein (GDAP1). The function of GDAP1 is unknown but mutations in this gene
have been associated with a severe recessive form of the neurological disorder Chacot-Marie-Tooth (CMT)
disease. In our studies we expressed recombinant GDAP1 in E. coli. We have not found any evidence that
GDAP1 has GST-like enzymatic activity but we have shown that it is generally membrane bound and is found
in a range of neural and non-neural tissues. ,
Expected future outcomes:
The studies of the metabolism of dichloroacetic acid by GSTZ1-1 have led us to more extensive investigations
of the effectiveness and potential side effects of DCA in cancer therapy. This work has provided basic
preclinical data required to support the use of DCA in clinical trials. , In the future we expect to complete the
structure of GDAP1.
Name of contact:
Prof Philip Board
Email/Phone no. of contact:
Philip.Board@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 316959
Start Year: 2005
CIA Name: Prof Robert Saint
End Year: 2007
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $409,500
Title of research award:
Analysis of Rho GTPase signalling pathways in an epithelial to mesenchymal transition during development of
the mesodermAnalysis of Rho GTPase signalling pathways in an epithelial to mesenchymal transition during
development of the mesoderm
Lay Description (from application):
A critical step in the progression of cancers that are derived from epithelial tissues is a transition from an
epithelial cell type to a migratory mesenchymal cell type that can spread to other parts of the body. This
change in cell behaviour also occurs, apparently by a similar mechanism, during the development of some
normal tissue types. Here we propose to use an animal model of this process, coupled with advanced molecular
genetic and cell biological techniques, to investigate a newly discovered cell signalling mechanism required for
the transition of cells from an epithelial form to a mesenchymal form. Understanding the molecular steps in this
new pathway and discovering new genes involved will provide tools for understanding and preventing the
metastasis of cancer cells.
Research achievements (from final report):
In this project we investigated how embryonic cells break free from their neighbours and start moving through
an embryo. Using a special photoactivatable fluorescently-tagged molecule (PAGFP) we saw, for the first time,
the dissociation and migration of mesodermal cells - the cells that eventually give rise to tissues like muscles,
heart and blood. We discovered that mesodermal cells use a surprising range of strategies to spread out
including migration as a group, pushing in between other cells and crawling over each other. We also
developed a way of tracking individual cells, a major technical advance. Our new techniques are now in high
demand from Australian and international laboraties. In addition to this cellular analysis, we explored the role
of a key signalling protein that is required for mesoderm migration. Studying this protein is complicated
because it also plays a role during cell division. To find out which parts of the protein were specifically needed
for migration we removed different regions of the protein. Removal of one region, which is needed for
membrane localisation, did not greatly affect cell division, but substantially affected cell migration. Using
genetic analysis, we also discovered other molecules involved in cell migration. With PAGFP as our new
diagnostic tool we have started exploring exactly what goes wrong in embryos lacking key regulatory genes .
Our discoveries will shed light on what role the corresponding genes play in similar processes, such as tumour
metastasis, that occur in humans.
Expected future outcomes:
We have established systems in which we can apply live imaging and genetic analysis to the nature of the
transition of cells to a migratory form, opening the way for a much more detailed analysis of this important
process.
Name of contact:
Robert Saint
Email/Phone no. of contact:
robert.saint@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 316977
CIA Name: Dr Lixin Rui
Admin Inst: Australian National University
Main RFCD: Tumour Immunology
Total funding: $335,245
Start Year: 2005
End Year: 2010
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
The role of the NF-kB pathway in primary mediastinal B cell lymphomaThe role of the NF-kB pathway in
primary mediastinal B cell lymphoma
Lay Description (from application):
Not Available
Research achievements (from final report):
I have revealed a novel epigenetic mechanism underlying lymphomagenesis and identified several molecular
targets in two common types of lymphoma in young patients, termed primary mediastinal B-cell lymphoma
and Hodgkin lymphoma, which share common molecular and clinical features. I investigated one common
genetic alteration, chromosome 9p amplification. Using RNA interference library screen, DNA microarry and
next-generation sequencing technologies, I have discovered that the oncogene JAK2 is cooperated with a coamplified gene encoding histone demethylase JMJD2C to modulate cancer epigenome. This edigenetic
modulation leads to expression of a body of genes including c-myc, IRF4, JAK2 and JMJD2C, which promote
proliferation and survival of cancer cells. My work has been recently reported in Cancer Cell and has drawn
broad interest in the field since the paper is the seventh most read paper. In the same issue of Cancer Cell, Prof.
Jonathan Licht from Northwestern University Feinberg School of Medicine, USA wrote his preview and stated
that " Rui et al. identify JAK2 and JMJD2C as two contiguous, coamplified oncogenes in primary mediastinal
B cell and Hodgkin lymphoma. Together, JAK2 and JMJD2C induce major changes in chromatin structure and
gene expression. Targeting these proteins with small molecules represents a new avenue for therapy." I also
conducted functional analysis of two other genes in the 9p amplicon, PDL1 and PDL2, which are ligands for
PD1 in T cell inhibition. I generated a co-culture system and performed several functional assays. Co-culture of
the cells expressing PDL1 or PDL2 with T cells significantly impairs T cell function as evidenced by reduced
IL2 production. This work largely contributes to our understanding of how lymphoma cells can evade tumor
immunity, and suggests that antibodies that block the PD1 pathway may be effective for the treatment of these
lymphomas. This work was recently published in Nature, of which I was a co-author.
Expected future outcomes:
My work demonstrates an addiction of cancer cells to the co-amplified genes in the chromosome 9p24 region
and therefore each of these genes could be a potential therapeutic target. For example, the inhibitors for JAK2
and histone demethylase may be effective for the treatment of a variety of malignancies with 9p24
amplification.
Name of contact:
Dr Louis Staudt
Email/Phone no. of contact:
lstaudt@mail.nih.gov
NHMRC Research Achievements - SUMMARY
Grant ID: 358672
CIA Name: Dr Ann Hughes
Admin Inst: Australian National University
Main RFCD: Epidemiology
Total funding: $313,176
Start Year: 2005
End Year: 2011
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
Epidemiological studies of association between immune deficiency and cancer and sunlight and immunerelated disordersEpidemiological studies of association between immune deficiency and cancer and sunlight
and immune-related disorders
Lay Description (from application):
Not Available
Research achievements (from final report):
, Using data abstracted from medical records compiled as part of the largest and most comprehensive
population-based case-control study of paediatric cancers, the United Kingdom Childhood Cancer Study
(UKCCS), we investigated the relationship between allergy and childhood leukaemia. The findings provided
more insight into the possible determinants of leukaemia in children. UKCCS data were also used to examine
the potential role of clinically-diagnosed infections in infancy and development of eczema. Our findings
challenge the 'hygiene hypothesis', which is based on the notion that a lack of exposure to infections early in
life increases risk of allergic disease. , We examined the association between ultraviolet radiation (UVR) and
childhood allergy using individual-level data from the Ausimmune Study about sun exposure patterns and
vitamin D supplementation. The findings highlight the possibility that vitamin D production in the skin
following sunlight exposure and supplementation with oral doses of derived vitamin D may both be important
in allergy development., In two separate articles, we reviewed the evidence linking (i) the 'hygiene hypothesis'
to development of multiple sclerosis (MS) and (ii) Epstein-Barr virus (EBV) infection to MS risk and disease
progression and identified the gaps requiring further research. For the former, two areas of particular interest
are the potential role of helminthic infection and the role of early-life exposure to herpesviruses other than
EBV. For the latter, a key emerging feature is that it is important to examine not only the antibody titre but also
the specificity of the humoral immune response to EBV and better understand what determines this. The task,
now, is to achieve some consistency in the findings using sufficiently large sample sizes to have statistical
power, well-characterised MS and control populations and sophisticated laboratory techniques, in order to
progress our understanding.
Expected future outcomes:
A paper examining the role of the hygiene hypothesis in development of multiple sclerosis will be submitted
before the end of the year. There are also plans to investigate gene x environment interactions in the
Ausimmune Study data (ie. HLA-DR15 genotype x sibling exposure).
Name of contact:
Dr Ann Maree Hughes
Email/Phone no. of contact:
annmaree.hughes@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 366706
Start Year: 2006
CIA Name: Prof David Tremethick
End Year: 2008
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $509,268
Title of research award:
Mechanisms that underpin chromosome stabilityMechanisms that underpin chromosome stability
Lay Description (from application):
One of the most amazing engineering achievements in nature is how over 2 meters of genetic material (DNA)
can be compacted and squeezed nearly a million times to fit into a human cell. The remarkable structure that
achieves this is the chromosome. Fundamental to the survival of a multicellular organism is that the
chromosome is stably maintained throughout out the life of an organism. For example, defects in maintaining
chromosome stability can lead to aneuploidy (cells with an abnormal number of chromosomes), a feature
exhibited by many forms of cancer. This packaging of genomic DNA that produces a chromosome is achieved
by a complex scheme of folding. At the first level, DNA is first wrapped around a mixture of proteins (called
histones) to form a complete unit known as a nucleosome. About 30 million of these building blocks are
required in every human cell to compact our DNA. Higher, more complicated levels of organization exist in
which a linear array of nucleosomes fold to various extents to form distinct functional and structural domains.
Importantly, specialised chromosomal domains, like the telomere and centromere, are assembled that keep the
ends of the chromosomes stable and enable a chromosome to copy itself every time our cells divide and grow,
respectively. How a chromosome is divided into these different compartments remains a mystery. This
investigation will show that a key cellular mechanism that determines how the chromosome is organised into
stable domains is by changing the make-up of chromosomal domains through the replacement of histone
proteins with specialised forms of histones called variants . These histone variants control the way a linear
array of nucleosomes fold into complex three-dimensional structures to perform a specialised function. This
fundamental research will provide important new information on how chromosomes become unstable in
cancer. It will also enable new strategies, which stabilise the chromosome, to be explored.
Research achievements (from final report):
For any organism, maintaining the integrity of its genome is vital for survival. This is achieved by the
packaging of the genome into chromosomes. To maintain the long-term stability of chromosomes, distinct
structural and functional domains have evolved to ensure that the ends of chromosomes are not eroded away
(the telomere) and following cell division, each daughter cell receives only one copy of each chromosome (the
centromere). The consequences are drastic if these fundamental chromosomal domains fail to perform their
respective tasks.,
The underlying mechanism by which
these important specialised domains are established is through the regulation of higher-order chromatin
formation; the way a linear array of nucleosomes fold to different extents into a variety of different
conformations. Our discovery that the essential histone variant H2A.Z is a critical structural and functional
component of heterochromatin has provided us with a window of opportunity to study how the assembly of
specialised chromatin structures regulate centromere function., We showed that a key cellular mechanism that
determines how the chromosome is organised into stable domains is by changing the "make-up" of
chromosomal domains through the replacement of histone proteins with specialised forms of histones called
"variants". These histone variants control the way a linear array of nucleosomes fold into complex threedimensional structures to perform a specialised function. Specifically, we demonstrated that H2A.Z is essential
for chromosome segregation by being strategically located at sub-domains within the centromere and
surrounding regions to generate the 3D chromatin architecture required for proper centromere function.
Expected future outcomes:
Given that chromosome instability is intimately associated with many diseases states including cancer, this
work will generate new insights into how these diseases may arise through the loss of chromosome
organization and centromere integrity. In the future, this work may offer new strategies for treatment, like the
over expression of H2AZ, to stabilise the chromosome.
NHMRC Research Achievements - SUMMARY
Name of contact:
David Tremethick
Email/Phone no. of contact:
david.tremethick@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 366731
Start Year: 2006
CIA Name: Prof Philip Board
End Year: 2008
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $490,021
Title of research award:
Pharmacogenetic and structural investigation of the Omega class glutathione transferasesPharmacogenetic and
structural investigation of the Omega class glutathione transferases
Lay Description (from application):
Members of the family of enzymes known as glutathione transferases are known to be responsible for the
metabolism and detoxification of a wide range of compounds including therapeutic drugs and cancer causing
chemicals. Genetic variation in an individual's compliment of glutathione transferases can alter their response
to drug treatment or their susceptibility to cancer. The Omega class of glutathione transferases are important
because they are involved in the metabolism of arsenic and because they have been shown to influence the ageat-onset of both Alzheimer s and Parkinson s diseases. The present studies will investigate the structure and
function of different Omega class glutathione transferases and determine how they interact with arsenic based
drugs. These studies will attempt to determine why the toxicity of arsenic varies between individuals and aims
to prevent adverse reactions to arsenic containing drugs used in cancer therapy. These studies will also
investigate the mechanism by which the inheritance of certain forms of Omega class glutathione transferase
can affect the age at-onset of Alzheimer s disease and Parkinson s disease. The understanding of this
mechanism may provide the basis for a therapy that could delay or prevent the onset of these common diseases.
Research achievements (from final report):
This project has resulted in the discovery that the Omega class glutathione transferase GSTO1-1 is identical to
S-phenacylglutathione reductase. This allowed us to develop a novel highly specific biochemical assay for
GSTO1-1 activity. The use of this assay permitted the characterization of GSTO1-1 deficiency caused by the
polymorphic deletion of Glu155 or the substitution of Ala for Val 236. We were also able to use T47D breast
cancer cells that are deficient in GSTO1-1 and GSTO2-2 to show that although these enzymes can catalyse the
reduction of some methylated arsenic species, they do not change the cytotoxicity of arsenic trioxide that is
used in cancer therapy. In addition, our studies of mine-workers exposed to high levels of environmental
arsenic found that the inheritance of GSTO1-1 deficiency variants does not alter the urinary excretion of
arsenic. Our data indicates that genetic variation in GSTO1-1 is not a significant factor contributing to adverse
reactions to arsenic trioxide therapy. In this project we also determined the crystal structure of GSTO2-2 and
the polymorphic variant of GSTO1-1 with a deletion of Glu155. The structure of GSTO2-2 is very similar to
that of GSTO1-1 but the differences allowed us to identify residues that promote its high rate of
dehydroascorbate reductase activity.
Expected future outcomes:
The techniques developed in this study will allow the further investigation of the role of Omega class GSTs in
Alzheimer's disease.
Name of contact:
Philip Board
Email/Phone no. of contact:
Philip.Board@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 366771
Start Year: 2006
CIA Name: Prof Christopher Goodnow
End Year: 2008
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Humoral Immunology and Immunochemistry
Total funding: $536,628
Title of research award:
Mechanisms controlling antibody production by modulating B cell antigen receptor signallingMechanisms
controlling antibody production by modulating B cell antigen receptor signalling
Lay Description (from application):
This project will analyse mechanisms that regulate antibody production in health and disease. In health,
antibodies are normally made exclusively against infectious agents, providing long-lasting immunity.
Unknown errors in the control of antibody production result in autoimmune diseases such as systemic lupus or
rheumatoid arthritis, where antibodies are made against parts of our own bodies, or result in allergies where
antibodies are made against innocuous elements of our environment, or result in uncontrolled B cell
accumulation in lymphoma, leukemia and myeloma. In order to develop rational, specific methods for treating
these diseases, it is necessary to identify and understand the biochemical mechanisms that normally control
antibody formation against infectious agents, self components, and innocuous environmental agents. The
project focuses on defining the biochemical mechanisms by which the antibody-forming cells, B lymphocytes,
sense infectious, innocuous, or self components. These cells carry specific receptors that bind these
components and transmit signals into the B lymphocyte. The research will determine how different types of
signal are transmitted by the receptor so that, normally, large amounts of antibody are made against infectious
agents but very little antibody is made against self components, and that B cell accumulation is tightly limited.
By identifying how the types of signals are changed, the results of this project will reveal control mechanisms
that may be altered in autoimmunity, allergy, immune deficiency, or lymphoma, and that may be able to be
used as drug targets to cure these diseases.
Research achievements (from final report):
The study identified how the immune system's antibody-forming cells, B lymphocytes, diminish their capacity
to multiply and make antibody if this antibody reacts with parts of our own body, or enhance their capacity to
multiply and make antibody if this antibody has previously been proven to react with a foreign microbe. The
study provides fundamental insights into two central questions in all of immunology: how forbidden clones of
self-reactive cells are silenced, and how desired clones of microbe-fighting cells are able to make a greater and
more rapid response upon a second exposure to the same microbe. The results thus provide a mechanistic
understanding for future research to prevent and treat autoimmune diseases and to enhance the effectiveness
and longevity of immunization against infection.
Expected future outcomes:
We are continuing to define the components of the gene program that inactivates forbidden clones of B cells,
testing the function of key elements of the program and how they are altered by subtle inherited differences,
and expect to submit further high impact publications on this during 2009.
Name of contact:
Chris Goodnow
Email/Phone no. of contact:
Chris.Goodnow@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 366787
CIA Name: Dr Anneke Blackburn
Admin Inst: Australian National University
Main RFCD: Genetics not elsewhere classified
Total funding: $462,290
Start Year: 2006
End Year: 2011
Grant Type: Career Development Fellowships
Title of research award:
Investigation of novel mouse mammary tumour susceptibility loci in mice and humansInvestigation of novel
mouse mammary tumour susceptibility loci in mice and humans
Lay Description (from application):
Not Available
Research achievements (from final report):
(A) Familial breast cancer is a disease with complex causes, and in many families it is now recognised that
there is not a single gene that puts a person at high risk of developing breast cancer, but it is having several
genes together, each which contributes a small increase in risk, that leads to a strong family history of breast
cancer. Our work has identified variants in one of these genes, called DMBT1, which increases the risk by
~1.6-fold of developing breast cancer. This contributes to the increasing list of genetic variants that contribute
to breast cancer risk. We have developed a special susceptible mouse strain that will allow us to identify
additional genes involved in breast cancer risk. , (B) Breast cancer is also a complex disease to treat, as there
are many different forms of breast cancer. However, many cancer cells change their metabolism to allow for
rapid growth and improved survival. We have studied a drug called dichloroacetate (DCA) that targets the
altered metabolism in cancer cells, forcing them back to a more normal metabolic pattern. We have found that
DCA treatment can inhibit the growth of many different cancer cells, including a very invasive breast cancer in
rats. Changing metabolism with DCA can also improve the effectiveness of other anti-cancer drugs by reducing
cancer cell survival. DCA is a very safe drug and has potential to move quickly to the clinic for cancer patient
treatment.
Expected future outcomes:
(A) In the future, this list of genetic factors will be used to identify individuals at highest risk of developing
breast cancer, allowing breast cancer screening programs to target those who will benefit the most. , (B) With a
better understanding of which cancers to treat and which drugs to use DCA with, we are working towards
clinical trials for cancer treatment with DCA in Australia.
Name of contact:
Anneke Blackburn
Email/Phone no. of contact:
anneke.blackburn@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418008
Start Year: 2008
CIA Name: Dr Mark Hulett
End Year: 2009
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Immunology not elsewhere classified
Total funding: $455,670
Title of research award:
The function of histidine-rich glycoprotein in inflammation and cancerThe function of histidine-rich
glycoprotein in inflammation and cancer
Lay Description (from application):
This research proposal investiagtes the role of a molecule known as histidine-rich glycoprotein (HRG) in the
important diseases of cancer and inflammation. Inflammatory diseases can occur when the the normal checks
on the immune system breakdown resulting in attacks on the body leading to tissue damage (e.g rheumatoid
arthritis) and are significant contributors to morbidity and health costs in Australia. Cancer is the leading
cause of death in Australia (28.4% of deaths in 2003). HRG has been implicated in controlling important
aspects of inflammatory and cancer disease progression. Namely, HRG appears to regulate the formation and
clearance of substances known as immune complexes - the primary cause of tissue damage in this disease.
Furthermore, HRG may also control the process of cell invasion which is crucial for the migration of white
blood cells of the immune system (leukocytes) to sites of inflammation to combat infections, and is also an
important mechanism by which malignant tumour cells escape from primary tumour sites and spread
throughout the circulation to other sites in the body. It is this process that makes cancer such a deadly disease.
This study aims to define how HRG contributes to these important processes. This information may allow the
development of new therapeutic approaches for the treatment of inflammatory diseases and cancer.
Research achievements (from final report):
Histidine-rich glycoprotein is a serum protein found at a high level in the blood of humans and most
invertebrates. The aims of this study were to investigate the role of HRG in cancer and inflammatory disease.
The key outcomes of the study resulted in a better understanding of the role of HRG in a number of important
physiological and pathological settings, including inflammatory disease, necrotic cell clearance and leukocyte
migration. This work is significant as it generated high impact outcomes in the research field of immunology
and cancer by defining the mechanism of action of HRG in the above settings. The benefits arising from this
work are that it provides a foundation for further important research in to the role of HRG in disease towards
the development of potential new therapeutic targets for the treatment of inflammatory disease and cancer.
Expected future outcomes:
This work provides a platform for further important studies into the function of HRG in inflammatory disease
and cancer. Based on the findings from this grant the investigation of the in vivo function of HRG in
inflammation and cancer is warranted and will validate HRG as a potential therapeutic target.
Name of contact:
Dr Mark Hulett
Email/Phone no. of contact:
m.hulett@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418048
CIA Name: Prof Frances Shannon
Admin Inst: Australian National University
Main RFCD: Gene Expression
Total funding: $531,697
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
The role of c-Rel in controlling chromatin architecture and transcription networks in T lymphocytesThe role of
c-Rel in controlling chromatin architecture and transcription networks in T lymphocytes
Lay Description (from application):
The immune system is poised to respond to invading viruses or bacteria and eliminate them as efficiently as
possible. Incorrect activation of the immune system leads to chronic inflammation and autoimmunity. Immune
cells can also grow in an uncotrolled manner causing leukamia. The cells of the immune system recognise
pathogens and respond by altering the patterns of proteins produced by the cells allowing the system to
eliminate the invading organisms. The altered protein production patterns stem from changes in the gene
expression profile of the cells. The gene expression profile of the cell is determinded by the activity of proteins
called transcription factors. One such factor, c-Rel, has been implicated in allergy, autoimmunity, in transplant
rejection and in leukemia. The aim of this project is to study the function of c-Rel in T cells, an important cell
type in the immune system. The overall aim is to understand how c-Rel controls the gene expression profile of
T cells so that a rational basis for c-Rel as a drug target can be designed.
Research achievements (from final report):
, This grant facilitated the following achievements:, , The research carried out under this
grant resulted in a number of significant research findings which are detailed in Section B, Point 6. , The
grant enhanced the development of new genomics technologies and was a factor in leveraging funding for these
technologies at ANU and in the ACT., Four research articles (and one more
submitted and one in preparation) were published in high quality journals., -Training of two postgraduate
students was facilitated by this grant, The grant provided employment for
one postdoctoral fellow and one technical officer for 3 years., .
Expected future outcomes:
- two more publications will result from this grant, - another student will graduate with a PhD, - follow up
grant applications will be possible
Name of contact:
Prof Frances Shannon
Email/Phone no. of contact:
frances.shannon@canberra.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418100
CIA Name: A/Pr Narcissus Teoh
Admin Inst: Australian National University
Main RFCD: Hepatology
Total funding: $339,078
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
DNA repair mechanisms in the pathogenesis of hepatocellular carcinomaDNA repair mechanisms in the
pathogenesis of hepatocellular carcinoma
Lay Description (from application):
Hepatocellular carcinoma (HCC) or cancer originating in the liver ranks 5th in worldwide frequency among
tumours, and is the 3rd highest cause of cancer in our region. The incidence is increasing in most countries
including Australia, Japan and USA. The overall prognosis is poor, with >80% affected persons dying from
this disorder. The risk factors for HCC are well known and include chronic hepatitis B or C virus infection,
alcoholism and liver iron accumulation. Despite the vast amount of information available regarding these risk
factors, the way in which they alter normal liver cells to make them cancerous remains undefined. The
majority of liver cancers, regardless of cause, develop in severely scarred, or cirrhotic liver in the presence of
chronic liver inflammation. Such an environment causes liver cells, which are usually stable and not dividing,
to continue replicating in response to injury; such continued cell division can lead to damaged genetic
information in the DNA of these cells. Many cancers are associated with chromosomal damage, including
broken ends and deleted genetic material. The main focus of this project to investigate how defective repair of
disrupted genetic information contained in DNA of chromosomes in damaged liver cells contributes to the
development of liver cancer. Using mice lacking specific genetic information to repair DNA double strand
breaks, we plan to investigate whether abnormalities in DNA repair mechanisms in liver cells damaged by
diethylnitrosamine (DEN) predisposes liver cells to regenerate abnormally thereby progressing to cancer. We
have clues that 7 specific sites in chromosomes where loss of key genes may promote HCC formation. These
studies will greatly enhance our understanding of the molecular basis by which HCC develops. The ultimate
goal of this research is to develop effective screening and treatment strategies to prevent or interrupt the
process of liver cancer development in at-risk individuals.
Research achievements (from final report):
The salient and novel observations that have arisen from the above project were:, o
A defect in the
Ku70 gene, a component of the non-homologous end joining DNA repair pathway, causes multiple
chromosomal abnormalities and accelerates liver cancer development in mice injected with the carcinogenic
agent, diethylnitrosamine. , o
The molecular basis of liver cancer
development in these mice lie in the failure of 'checkpoint' mechanisms in liver cells - with the loss of p53, a
key cancer suppressor in liver cells, they proliferate out of control. , o
These mouse liver cancers show high
expression of Aurora A kinase, phospho-ATM, mdm2, and ubiquitination activity - these biological features
highly resemble human primary liver cancer. In other words, we have a mouse model of liver cancer that is
biologically similar to human liver cancer - such a model would be very useful for further molecular
mechanistic studies., We have identified a suite of 9 novel genes through chromosomal array analysis that that
may help explain how abnormal chromosomes in damaged liver cells can cause them to turn into cancer cells.
Expected future outcomes:
This exciting work continues with plans underway for translational research to commence in human HCCs .
Name of contact:
Narci Teoh
Email/Phone no. of contact:
narci.teoh@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 471409
CIA Name: Prof Emily Banks
Admin Inst: Australian National University
Main RFCD: Epidemiology
Total funding: $570,218
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Research Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am an epidemiologist using large scale cohort study methods to investigate potentially modifiable factors
affecting common conditions, particularly those related to ageing.
Research achievements (from final report):
Over the 2008-2012 period of the fellowship, I have achieved the following in terms of traditional research
outputs:- 86 articles in peer-reviewed journals- Chief Investigator on grants totalling $16 million; $9 million as
CIA- an h-index of 32 (source: Google Scholar)- awards for career achievement, media engagement and
research translation- peer-recognition in the form of invited editorials in leading journals in the field and
speaking invitations at national and international conferences.The fellowship has also led to significant
achievements in building research infrastructure. As Scientific Director, I continue to provide scientific
leadership of the 45 and Up Study. The study completed recruitment of 267,153 participants in late 2008,
making it the largest study of its kind in the Southern Hemisphere. It is a collaborative research resource with
now: over 450 researchers currently using the data (61 early career); 114 research projects approved and over
$13 million in competitive project-specfic funds leveraged. I provided epidemiological leadership of the
SEARCH Study of urban Aboriginal children, which is also the largest study of its kind ever conducted and
will provide new insights relevant to this important and under-researched group. Over the period of the
fellowship I became the founding head of the Chronic Disease Epidemiology Group at the National Centre for
Epidemiology and Population Health and was promoted to Professor at the Australian National University. I
was a member of a range of important committees, including the Quality Advisory Committee and State
Accreditation Committee for Breast Screen ACT and SE NSW and the Research Advisory Committee of the
National Breast Cancer Foundation. I also received a Ministerial appointment as the inaugural Chair of the
Advisory Committee on the Safety of Medicines. I have supervised 9 PhD students to date and have mentored
and supervised 15 postdoctoral fellows and early career researchers.
Expected future outcomes:
The foundations laid by the work completed during the fellowship are expected to contribute to future policyrelevant work on pharmacoepidemiology, Aboriginal health and healthy ageing. There will be continuing
emphasis on building quality research infrastructure and on training and mentoring of early career researchers.
Name of contact:
Emily Banks
Email/Phone no. of contact:
emily.banks@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 471416
CIA Name: Prof Frances Shannon
Admin Inst: Australian National University
Main RFCD: Gene Expression
Total funding: $619,805
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Epigenomic marks as indicators of the kinetics of gene activation in immune cells.Epigenomic marks as
indicators of the kinetics of gene activation in immune cells.
Lay Description (from application):
Switching on an immune response involves major changes in the gene expression program of the immune cells.
These changes in gene expression take place in the context of DNA packaged into the nucleus in a structure
known as chromatin. We will investigate the relationship between chromatin and gene expression changes and
how this relationship plays a role in the timing of the immune response. This information will be useful in
developing novel means of controlling aberrant immune responses.
Research achievements (from final report):
The response of immune cells to fight a range of infections is critical to maintaining health. A core aspect of
the response of immune cells is their ability to switch on the expression of a particular set of genes required to
respond to a specific infection. On the other hand, pathological autoimmune responses involve the
inappropriate expression of immune genes. Switching on the expression of genes takes place in the nucleus in
the context of a complex molecular structure known as chromatin. This project used sequencing technology to
map the chromatin "marks" on genes that are destined to be activated when immune cells detect an infection.
The findings showed us that genes that are destined to be activated in immune cells are tagged in a specific
manner meaning that they response quicker and easier than genes without these specific tags. We found that the
machinery required for the expression of these genes is in fact already loaded onto the gene but is "stalled" or
"poised" for activation. This finding is in line with studies in other systems which is now showing that this a
common mechanism by which genes are marked for response to specific external signals.
Expected future outcomes:
This work has increased our understanding of gene expression in immune cells.The implications of this work
are that may be possible target this stalled form of the transcription machinery either to provide for more
efficient activation of the immune system when required to fight infections or to block immune activation in
cases where such activation is detrimental such as in autoimmune responses
Name of contact:
Prof Frances Shannon
Email/Phone no. of contact:
frances.shannon@canberra.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 471422
Start Year: 2008
CIA Name: Prof David Tremethick
End Year: 2012
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $589,425
Title of research award:
Regulation of the histone code by histone variantsRegulation of the histone code by histone variants
Lay Description (from application):
A fundamental unanswered question in biology is how a single fertilized mammalian cell can differentiate into
a multicellular organism when every differentiated cell type inherits the same DNA. Fundamental to this
development process is that different sets of genes are expressed in different cell types. This investigation will
show that a key mechanism to regulate gene expression is the way our DNA is covered with specifically
modified and altered forms of histone proteins.
Research achievements (from final report):
It is now clearly established that the dynamic packaging of DNA into chromatin regulates all aspects of
genome function by altering the accessibility of DNA to DNA-dependent machineries that copy, repair or
express our genome. Chromatin is built from nucleosomes, the universal repeating protein-DNA complex in all
eukaryotic cells. A nucleosome is comprised of two tight superhelical turns of DNA wrapped around a diskshaped protein assembly of eight histone molecules (two molecules each of histone H2A, H2B, H3, and H4).
Different epigenetic mechanisms have been described that alter the structure of the nucleosome to regulate
genome function, which include an extensive range of enzyme-catalysed modifications of site-specific amino
acid residues on the N-terminal tail of each histone, and altering the biochemical composition of a nucleosome
by the substitution of one or more of the core histones with their variant forms.,
Our work
demonstarted that the exchange of H2A with its variants represents one of the most dramatic and essential
alterations to the structure and function of chromatin by being required for regulation of transcription and to
establish gene expression programs during differentiation. Specifically, we discovered a new histone variant,
H2A.Lap1, which plays a fundamental role in controlling gene expression during mouse spermatogeneis. We
made the remarkable discovery that H2A.Lap1-containing nucleosomes are a novel component of active
chromatin being involved in a new mechanism of gene expression control whereby H2A.Lap1 co-ordinately
activates the expression of many genes by being targeted and directly opening the chromatin structure at their
transcription start sites.
Expected future outcomes:
Approximately 7.5% of human males are infertile but despite substantial efforts, the causes of spermatogenetic
failures still remain largely unknown. Given that we have characterized how gene regulation occurs during
mouse spermatogenesis, this will form the basis to look at what happens in humans.
Name of contact:
David Tremethick
Email/Phone no. of contact:
david.tremethick@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 471439
CIA Name: Prof Carola Vinuesa
Admin Inst: Australian National University
Main RFCD: Autoimmunity
Total funding: $495,467
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Genetic pathology of Roquin in human autoimmune diseaseGenetic pathology of Roquin in human
autoimmune disease
Lay Description (from application):
Lupus is a life-threatening disease in which immune responses normally targeted at germs are directed at tissue
in the body. We have discovered a mouse model of lupus and elucidated an important pathway that determines
whether immunity is directed at the body or at germs. Building on recent progress in understanding the genetic
variation between individuals, we will use the information obtained from the mouse model to investigate the
genes that regulate this pathway in people with lupus.
Research achievements (from final report):
We have consolidated and expanded a repository of DNA samples from patients with systemic lupus
erythematosus (SLE). This "APOSLE" collection counts today with ~ 260 DNA samples from Australian SLE
patients and a similar number of controls. A simple blood-based cell phenotype screen has also been
established using flow cytometric analysis and a 4 antibody combination. This allowed identification of a tight
correlation between high numbers of circulating Tfh cells and severity of lupus phenotype in a subset of SLE
patients. We have also identified several mutations in several microRNAs in SLE and CVID patients, as well
as copy number variations in genes predicted to dysregulate T and B cell activation. These findings should
have diagnostic and therapeutic implications. We are currently performing functional assays to evaluate the
significance of the mutations/SNPs and CNVs we have identified.,
Expected future outcomes:
It is expected that the discoveries of gene variants predisposing to lupus will help diagonose and stratify lupus
patients for specific treatment targeting the dysfunctional pathway. Increased understanding of the molecular
pathways that cause lupus is also expected to help identify novel drug targets.
Name of contact:
Anastasia Wilson (Project Nurse)
Email/Phone no. of contact:
anastasia.wilson@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 471491
CIA Name: Dr Mark Clements
Admin Inst: Australian National University
Main RFCD: Epidemiology
Total funding: $380,559
Start Year: 2008
End Year: 2011
Grant Type: Career Development Fellowships
Title of research award:
Population health modelling, with applicationsto asbestos-related diseases, cervical cancer and prostate
cancerPopulation health modelling, with applicationsto asbestos-related diseases, cervical cancer and prostate
cancer
Lay Description (from application):
Population health modelling can be used to understand complex systems, through bringing together diverse
data sources to answer questions of public health importance. We will apply modelling techniques to three
public health areas, including: the effects of HPV testing on cervical cancer screening; the impact of the rapid
uptake of PSA screening on prostate cancer incidence and mortality; and projections of the incidence of
asbestos-related diseases.
Research achievements (from final report):
We have: (i) further developed a Markov model for cervical cancer screening for Australia; (ii) received
funding and initiated development of a prostate cancer model for Australia; and (iii) published on prostate
cancer, cervical cancer, mesothelioma projections, ultraviolet radiation exposure, avian influenza, disinfection
byproducts, socioeconomic status and methods developments.
Expected future outcomes:
We will continue population-level modelling of prostate and cervical cancer in Australia, together with the
development of statistical methods for the analysis of linked data.
Name of contact:
Mark Clements
Email/Phone no. of contact:
mark.clements@ki.se
NHMRC Research Achievements - SUMMARY
Grant ID: 471498
Start Year: 2008
CIA Name: Dr Adam Cook
End Year: 2013
Admin Inst: Australian National University
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $371,603
Title of research award:
The role of the chaperone NASP in regulating histone dynamics during DNA replication and repairThe role of
the chaperone NASP in regulating histone dynamics during DNA replication and repair
Lay Description (from application):
To fit inside our cells, DNA is intricately packaged with histone proteins into chromatin. All aspects of cell
function are regulated by this packaging. My research will help us to understand how the cellular life of
histones is controlled by a protein called NASP to ensure the packaging is correctly maintained and reorganised
during normal genome function.
Research achievements (from final report):
Packaging over two metres of DNA into each of our cells, histone proteins regulate the function and integrity
of our genome. To ensure histones are handled properly throughout their cellular life, thereby preventing
abnormal gene function and cancer, they are escorted by chaperone proteins. I discovered that one chaperone,
NASP, whose function is altered in cancer cells, has a unique role in escorting histones in human cells and
regulating histone supply. My work has provided new insights into the means by which the histone supply is
regulated in mammals, notably how unwanted or excess histones are eliminated by the cell's internal protein
degradation machinery. My findings have made an important contribution to understanding the fundamental
means of packaging our genome to protect it against damaging insults and have provided the first clue as to the
role NASP plays in cancer. I anticipate that elucidating the role of NASP and regulation of histone metabolism
will open up new avenues for identifying noval prognostic factors in cancer and understanding the origins of
cancer.
Expected future outcomes:
In prompting a major re-evaluation of how the dynamics and metabolism of the proteins that package our
genome are regulated, I expect that this work will lead both to significant new advances in understanding
genome function and the identification of new cancer markers and therepeutic targets.
Name of contact:
Dr Adam Cook
Email/Phone no. of contact:
a.cook@centenary.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 471503
CIA Name: Dr Elizabeth Murchison
Admin Inst: Australian National University
Main RFCD: Genome Structure
Total funding: $210,855
Start Year: 2008
End Year: 2013
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
Genomic approaches to understanding Tasmanian devil facial tumor diseaseGenomic approaches to
understanding Tasmanian devil facial tumor disease
Lay Description (from application):
Devil facial tumor disease (DFTD) is an emerging infectious disease affecting Tasmanian devils. DFTD is a
transmissible cancer, and results in the growth of large tumors usually on the face and mouth of affected
animals. DFTD has led to the collapse of the Tasmanian devil population, and there is concern that the disease
will drive devils to extinction in the wild within the next 20 years. I propose to use new genome sequencing
technologies to discover genes responsible for DFTD.
Research achievements (from final report):
This research award supported the sequencing, assembly and annotation of the Tasmanian devil genome. It also
led to the sequencing of the genome of Tasmanian devil facial tumour disease (DFTD). This was the first
marsupial cancer to be sequenced and revealed that the cancer arose from a female Tasmanian devil that lived
relatively recently, probably in Eastern Tasmania. The cancer that it spawned has diverged widely through the
devil population and has acquired approximately 20,000 mutations during its evolution. DFTD has spread
rapidly through the devil population, and we found evidence for a founder tumour population on the remote
Forestier Peninsula. The Forestier Peninsula DFTD population has undergone a lineage replacement, possibly
caused by a selective sweep. We found evidence for frequent reinfection of devils with DFTD, indicating that,
at least in some cases, DFTD infection does not prevent reinfection upon a second challenge. This research also
resulted in the identification of the Schwann cell origin of DFTD and development of Periaxin, a Schwann cell
marker, as a diagnostic marker for DFTD. This research has provided a starting point for understanding the
genetic basis of DFTD's transmissibility and has provided important genetic tools for Tasmanian devil genetics.
Expected future outcomes:
Future outcomes may include development of a DFTD preclinical diagnostic test based on serum DNA as well
as further understanding of DFTD immune evasion mechanisms and understanding of patterns of DFTD
evolution and spread. These insights may lead to greater understanding of cancer evolution and immune
evasion in human cancer.
Name of contact:
Elizabeth Murchison
Email/Phone no. of contact:
epm27@cam.ac.uk
NHMRC Research Achievements - SUMMARY
Grant ID: 471512
Start Year: 2008
CIA Name: Dr Ross Stephens
End Year: 2009
Admin Inst: Australian National University
Grant Type: NHMRC Development Grants
Main RFCD: Radiotherapy and Nuclear Medicine
Total funding: $170,717
Title of research award:
Novel nanoparticle composites for molecular probes in diagnostic imagingNovel nanoparticle composites for
molecular probes in diagnostic imaging
Lay Description (from application):
Isotope labelled protein probes, eg. antibodies, are a valuable imaging tool in investigating patient disease.
Their biological specificity is their great strength, however, detection sensitivity often limits their use. A novel
nanoparticle developed at ANU can increase this signal by a million-fold in comparison with conventional
methods of labelling. This approach suits a range of probes and will accommodate many of the isotopes already
used in patient diagnostics and therapy.
Research achievements (from final report):
The grant from NHMRC has enabled initial development studies of our novel radiolabelled nanoparticle
technology for applications in nuclear medicine. The principal outcomes sought were discovery and testing of
reliable new methods for attaching macromolecules and especially biological substances to the outside surface
of graphitic nanoparticles that have radioactive cores, such that the biological coatings do not detach from the
radiolabelled nanoparticles under conditions experienced inside the body. We have been successful in
achieving this outcome for proteins, notably antibody coatings, and also in developing methods for attaching
the protein coated nanoparticles to synthetic polymers, such as those used in oncology as devices for
administering internal radiation therapy. The development studies have employed a clinical gamma camera to
image the biodistribution of radiolabelled nanoparticle composites in animal models, and their accumulation at
different organ sites., , The positive outcomes obtained in this study have strengthened our collaboration with a
commercial partner active in the medical oncology field, so that it is planned that the technology will be further
developed and tested for its potential application in the assessment of cancer patients prior to their cancer
treatment.
Expected future outcomes:
The future outcomes from this project may include novel nanoparticle composites enabling better imaging of
tumours that will improve assessment of staging and treatment efficacy for cancer patients. Further
development of the nanoparticle technology may also lead to better targeted therapy.
Name of contact:
Dr Ross Stephens
Email/Phone no. of contact:
ross.stephens@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 514904
CIA Name: Prof Thomas Preiss
Admin Inst: Australian National University
Main RFCD: Gene Expression
Total funding: $770,255
Start Year: 2008
End Year: 2013
Grant Type: NHMRC Research Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a molecular biologist determining the mechanisms of eukaryotic mRNA translation and its regulation by
RNA-binding proteins and noncoding RNA. In collaborative work I extend these basic science objectives into
the medical research areas of cardiology
Research achievements (from final report):
Research Record: Since 2008 I have authored twenty research articles (highlights: Cell, Mol Cell, Mol Cell
Proteomics, Nat Med, Nat Chem Biol, Nucleic Acids Res Featured Article), 9 reviews and five book chapters.
In 2008 I filed a provisional patent application (discontinued)., Grant Support: I have attracted eight NHMRC
project grants (seven as CIA), four miscellaneous grants, and two ARC Discovery grants to fund my work.,
Peer Recognition: I have given plenary talks at international meetings, and spoke or chaired sessions at
multiple national conferences. I have given talks at regional meetings and symposia and frequently gave
institutional and departmental seminars. A highlight has been my role in organising the Lorne Genome
conference from 2010-13. I have been co-chair (2010) and chair (2011) of the national organising committee.
In 2014 I was awarded the Julian Wells Medal. In 2011 I was appointed as Professor of RNA Biology at ANU.,
Research Training: I have trained nine PhD students and three Honours students (both completed), as well as
more senior research staff. I have lectured undergraduate students in RNA Biology at UNSW and more
recently at ANU., Professional Activities: I am active in peer review, as an editor of and reviewer for scientific
journals, and as a grant assessor for national and international funding bodies. I am an active member of
relevant professional societies. Of particular note, I co-founded and presently chair the RNA network
Australasia, a special interest group (SIG) of the Australian Society for Biochemistry and Molecular Biology
(ASBMB).
Expected future outcomes:
I am fully engaged in active research and currently have six manuscript submitted for publication. Three
further papers are currently in preparation. All of this work stems at least in part still from the time that I was
funded by the SRF.
Name of contact:
Thomas Preiss
Email/Phone no. of contact:
thomas.preiss@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 525424
Start Year: 2009
CIA Name: Prof David Tremethick
End Year: 2012
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $521,592
Title of research award:
The organisation of the chromosome into distinct epigenetic domains and its link with development and
diseaseThe organisation of the chromosome into distinct epigenetic domains and its link with development and
disease
Lay Description (from application):
This investigation will show that a key cellular mechanism that determines how the chromosome is organised
into stable domains is by changing the make-up of chromosomal domains through the replacement of histone
proteins with specialised forms of histones called variants . This fundamental research will provide important
new information on how chromosomes become unstable in cancer.
Research achievements (from final report):
For any organism, maintaining the integrity of its genome is vital for survival. Indeed, chromosome instability
is a hallmark of malignant cancer but the molecular mechanism(s) that leads to this instability is poorly
understood. The overall hypothesis for this grant was that H2A.Z plays a key role in organising the genome
into distinct 3-D structures and this regulation by H2A.Z is altered in cancer. To test this hypothesis our aims
were to: (1) carry out an extensive 2-D and 3-D structural and epigenetic analysis of all human centromere
regions both in control and cancerous cells, (2) investigate the role of H2A.Z in cancer and (3) elucidate the
role of H2A.Z-containing heterochromatin in repressing retrotransposon elements. Overall, we have found that
there are global epigenetic changes to chromosome architecture during cancer progression. Specifically, we
have provided new insights into how the chromosome is organised into distinct epigenetic domains, how
chromosomes become destabilised during malignant transformation and that this was linked with changes to
the abundance of H2A.Z at their heterochromatic domains. Finally, we uncovered a new important role for
H2A.Z in regulating LINE expression, which changes during development and cancer.
Expected future outcomes:
We believe our work could lead to the development of a new simple diagnostic test for cancer progression.
This test would involve the simple immunofluorescence analysis of H2A.Z-containing heterochromatin on
those specific human chromosomes that lose H2A.Z and become disrupted when cancer cells become
metastatic.
Name of contact:
David Tremethick
Email/Phone no. of contact:
david.tremethick@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 525458
Start Year: 2009
CIA Name: Prof Philip Board
End Year: 2012
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $433,901
Title of research award:
The evaluation of gamma-glutamylcyclotransferase as a novel target for cancer therapy and diagnosisThe
evaluation of gamma-glutamylcyclotransferase as a novel target for cancer therapy and diagnosis
Lay Description (from application):
Gamma glutamylcyclotransferase (GGCT) plays a pivotal role in regulating the synthesis of glutathione, a
compound that is essential for life and regulates many intracellular processes. Several recent studies have
shown that GGCT is highly expressed in cancer cells . This study will determine if GGCT is a target for cancer
chemotherapy or if it can be used for cancer diagnosis. This study may also provide a new treatment for
patients with glutathione synthetase deficiency.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 525473
CIA Name: Dr Claire Larter
Admin Inst: Australian National University
Main RFCD: Gastroenterology and Hepatology
Total funding: $199,486
Start Year: 2009
End Year: 2013
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Obesity, insulin resistance and hepatocarcinogenesis: metabolic mediators and molecular mechanismsObesity,
insulin resistance and hepatocarcinogenesis: metabolic mediators and molecular mechanisms
Lay Description (from application):
Liver cancer (or hepatocellular carcinoma, HCC) is the 3rd most common cause of cancer death, with the
incidence in Australia increasing. Recently, it has been shown that obesity, diabetes and fatty liver disease can
lead to HCC; this project will explore how metabolic diseases promote HCC. The role of insulin and fatty acids
in promoting DNA damage and cell growth will be examined. Understanding how metabolic disease increases
HCC risk will improve prevention strategies and possible treatments.
Research achievements (from final report):
This project provided some validated that liver cancer development is accelerated in genetically obese animals,
and that dietary composition may alter liver cancer development.
Expected future outcomes:
N/A
Name of contact:
Claire Larter
Email/Phone no. of contact:
claire.larter@gmail.com
NHMRC Research Achievements - SUMMARY
Grant ID: 585414
CIA Name: Prof Geoffrey Farrell
Admin Inst: Australian National University
Main RFCD: Gastroenterology and Hepatology
Total funding: $424,262
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The Bidirectional Liver TRAILThe Bidirectional Liver TRAIL
Lay Description (from application):
Liver damage after liver surgery or shock is called ischemia-reperfusion injury (IRI). Recovery after surgical
removal of liver tissue is due to liver regeneration. IRI and liver regeneration are controlled by specialised
proteins called cytokines, one of which, TRAIL, is essential for both IRI and liver regeneration. This research
is to find out how TRAIL exerts such seemingly opposite effects. The aim is to learn how to protect the liver
against damage, and to stimulate its recovery.
Research achievements (from final report):
We have discovered the critical importance of 2 signaling molecules in causing liver injury after surgery
(ischemia-reperfusion liver injury). These are called TRAIL (TNF-like receptor apoptosis-inducing ligand) and
its receptor on cells called "Mouse Killer". Mice lacking either TRAIL or Killer are completely protected from
liver ischemia reperfusion injury. Further, when ordinary (wildtype) mice were given a bone marrow transplant
with cells from either TRAIL or Killer genetically deleted mice, these "bone marrow chimeras" were similarly
protected against ischemia-reperfusion injury. We are now in a position to determine the precise type of cell
that recognises conditions that "switch on" this pattern of severe tissue injury.
Expected future outcomes:
We expect to isolate the one or more critical cells that initiate liver ischemia-reperfusion injury, and this would
allow therapeutic manipulations to protect livers from this devastating complication of liver surgery and liver
transplanation.
Name of contact:
Professor Geoff Farrell
Email/Phone no. of contact:
geoff.farrell@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350446
Start Year: 2005
CIA Name: A/Pr Susan Nilsson
End Year: 2007
Admin Inst: Australian Stem Cell Centre Ltd
Grant Type: NHMRC Project Grants
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $472,063
Title of research award:
The role of hyaluronic acid, CD44 and osteopontin in haemopoietic stem cell biologyThe role of hyaluronic
acid, CD44 and osteopontin in haemopoietic stem cell biology
Lay Description (from application):
Marrow and microenvironmental cell (MC) interactions play a central role in bone marrow (BM) cell
localisation and regulation. Specifically, the regulation of primitive blood cells (HSC) is affected by their
locality and their expression of a wide repertoire of cell adhesion molecules. This project is based upon the
unique observations made in the applicants laboratory demonstrating that the three molecules hyaluronic acid
(HA), CD44 and osteopontin play key roles in the localisation of HSC within the BM following transplantation
and in regulating their development into mature blood cells. Encapsulating the concept of highly specific, local
interactions regulating blood cells is the 'niche' hypothesis in which MC form a specific 'niche'. The current
inability to identify HSC in situ makes it impossible to analyse either their distribution or molecules that
regulate this process. Circumstantial evidence suggests the presence of HSC 'niches' in close association with
the bone. Using a novel approach based on BM transplantation to track cells lodging in the BM, we were the
first to report that the lodgement of a transplanted HSC is not a random process, but results in cells of donor
origin migrating to the bone/marrow interface. The presence of HA and CD44 on the HSC and CD44 and
ostepontin in the marrow microenvironment are critical for this pattern of lodgement. In addition, we now have
evidence that HA and osteopontin are important in the maintenance of HSC in their primitive state. This
proposal aims to confirm the critical roles and interactions of these three molecules in HSC biology.
Research achievements (from final report):
This research project provided new insights into how blood forming stem cells are regulated by their immediate
environment within the bone marrow. The research focused on how two molecules independently regulate
blood stem cells. The first molecule, hyaluronic acid, which is comprised of multiple repeats of two simple
sugars is expressed by hemopoietic stem cells and other cells within the environment. The biology of
hyaluronic acid is intriguing because the same sugars can be synthesized by three different synthases and
showed the sugar made by only one of these is critical for the homing, lodgement and regulation of stem cells
in the bone marrow. In addition, the second protein made by cells that line the inner surface of the bone
marrow cavity, osteopontin, is also critical for the homing, lodgement and regulation of stem cells in the bone
marrow. Both of these molecules act to maintain stem cells in a non-dividing primitive state.
Expected future outcomes:
This research has provided us with a better understanding of the bone marrow environment and how this
regulates adult marrow stem cells. This can lead to improvements in bone marrow transplants and the
manipulation of adult marrow stem cells for purposes such as directed blood cell formation in the development
of cellular products.
Name of contact:
Susie Nilsson
Email/Phone no. of contact:
susie.nilsson@stemcellcentre.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 268905
Start Year: 2004
CIA Name: A/Pr Assam El-Osta
End Year: 2006
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $254,250
Title of research award:
A new paradigm for SWI/SNF chromatin function; the ATPase dependent remodeler is a component of the
MeCP2 complexA new paradigm for SWI/SNF chromatin function; the ATPase dependent remodeler is a
component of the MeCP2 complex
Lay Description (from application):
DNA methylation is a major determinant in the epigenetic silencing of many genes. The mechanisms
underlying that targeting of DNA methylation and the consequence, that is, transcriptional silencing are
relevant to human development and disease. Examples of the significance of alterations in the controls of DNA
methylation and histone deacetylation in human disease include mental retardation (fragile X syndrome, Rett
syndrome) and carcinogenesis. Evidence is emerging that a family of methylation specific (methyl-CpG
binding domain, MBD) proteins have the capacity to bind to methylated sequences and repress transcription.
The mechanisms that target CpG methylation however still remain unclear. Furthermore, it is becoming
increasingly evident that methyl-CpG binding proteins are not alone in silencing transcription and other
epigenetic components are thought to influence transcription (namely, SWI/SNF activation complex). This
grant proposal concentrates on our most recent work which demonstrates a new molecular mechanism of
transcriptional repression extending the mechanism mediated by MeCP2. Our results are the first to show that
the human SWI/SNF ATPase complex is a transcriptional repressor and is identified as part of the MeCP2histone deacetylase repressor complex. This data extends the mechanistic link between DNA methylation,
chromatin remodelling and transcriptional regulation. More importantly, the experimental findings could lead
to a re-examination of the mechanistic basis behind MeCP2 transcriptional repression and epigenetic
modification. Our findings suggest a new paradigm for SWI/SNF as a component of the MeCP2 methylation
dependent silencing complex.
Research achievements (from final report):
Epigenetics is a term that refers to changes to the genome in the absence of genetic mutation. This has a
profound consequence on the behaviour of genes relevant to normal human development and also has been
associated with disease. This work has defined a unique protein interaction that is relevant to gene activity in
human cancer and mental retardation.
Expected future outcomes:
A better understanding of gene beahviour in human disease.
Name of contact:
Assam El-Osta
Email/Phone no. of contact:
assam.el-osta@baker.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 526648
Start Year: 2009
CIA Name: Dr Paul Gregorevic
End Year: 2011
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $557,478
Title of research award:
Defining mechanisms of follistatin-mediated muscle adaptation, for treatment of frailty and muscle-related
diseasesDefining mechanisms of follistatin-mediated muscle adaptation, for treatment of frailty and musclerelated diseases
Lay Description (from application):
Physical frailty-weakness is one of the most common symptoms of serious illness and a key cause of death. I
propose to study a new model of skeletal muscle growth, to learn more about the causes of wasting in musclerelated diseases. The work will identify cell mechanisms that cause loss of muscle strength, and will help
develop novel treatment approaches to prevent or reverse physical frailty in illness. New therapies to combat
frailty are vital to improve the health of our community.
Research achievements (from final report):
Over the course of this project we have made significant advances concerning the role of the Transforming
Growth Factor-beta signaling pathway as a regulator of skeletal muscle growth. Most notable has been the
elucidation of a mechanisms of interaction between the TGF-b signalling network and the PI3K/Akt/mTOR
which is required to stimualte the sysnthesis of protein in muscle cells. These findings have been published in
the prestigious Journal of Cell Biology, and other findings are presently being prepared for submission in other
research manuscripts. Our findings have identified important new aspects of the regulatory mechanisms that
operate within skeletal muscle.
Expected future outcomes:
We hope to submit another two research manusctips based on the work of this project in the next few months.
Collectively, the discoveries we have made have identified new therapeutic targets within the cell that we now
wish to ivestigate in follow-up research.
Name of contact:
Paul Gregorevic
Email/Phone no. of contact:
paul.gregorevic@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566559
Start Year: 2009
CIA Name: Dr Tom Karagiannis
End Year: 2012
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Radiotherapy and Nuclear Medicine
Total funding: $589,532
Title of research award:
DNA binding ligands for Auger therapy and receptor imagingDNA binding ligands for Auger therapy and
receptor imaging
Lay Description (from application):
Our aim is to develop new technologies for very specific cancer radiotherapy and diagnostic imaging. The
system involves the use of a protein linked to a radioactive DNA binding drug. The radioactivity we use has a
very small range -a few millionths of a millimetre- allowing us to selectively kill cancer cells with minimal
harm to healthy tissue. For diagnosis we use smaller amounts of radiation to obtain a clear image of the areas
and extent of disease, which facilitates appropriate treatment.
Research achievements (from final report):
We have developed a strategy for specifically targeting cancer cells for both therapeutic and imaging
(diagnostic) applications. Our approach involves targeting specific receptors on cancer cells to deliver a
radioactive DNA binding ligand. Decay of the radioactive atom on the DNA kills the target cells. By selecting
an appropriate radioactive atom - an Auger emitter - we can eradicate diseased cells while minimising damage
to normal surrounding tissue.
Expected future outcomes:
We will continue to develop and evaluate our targeting approach with the ultimate aim of clinical application.
We are investigating cutaneous and peripheral T-cell lymphomas as potential malignancies for our initial
preclinical studies.
Name of contact:
Tom Karagiannis
Email/Phone no. of contact:
tom.karagiannis@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1002663
Start Year: 2011
CIA Name: A/Pr Dianna Magliano
End Year: 2013
Admin Inst: Baker IDI Heart and Diabetes Institute Grant Type: NHMRC Project Grants
Main RFCD: Preventive Medicine
Total funding: $412,291
Title of research award:
The Australian and New Zealand Diabetes and Cancer CollaborationThe Australian and New Zealand Diabetes
and Cancer Collaboration
Lay Description (from application):
Diabetes, obesity, metabolic syndrome, hypertension and cancer are chronic diseases faced by many
Australians. There is some evidence to suggest that those with diabetes or are obese are at an increased risk of
cancer. Sufficiently large studies to examine these relationships do not exist in Australia. This project aims to
pool Australian and New Zealand longitudinal studies which have information on diabetes and obesity to
examine the relationship between diabetes, obesity and cancer.
Research achievements (from final report):
We have successfully linked one of the world's largest diabetes registries to obtain death and cancer outcomes
in almost 1.5 million people. This was a great achievement. Using this dataset, we have shown that mortality
from cancer is becoming an increasing burden among people with diabetes as treatment for cardiovascular
diasese improves. We also show a relatively large excess risk for many types of cancer in people with diabetes
compared to the general population. For type 1 diabetes, this has previously not been shown as most studies are
limited by small sample sizes. This work is particularly important in light of the current diabetes epidemic,
coincinding with an aging population allowing people to live long enough to get cancer. This means we are
likely to see a double burden of diabetes and cancer in the future if current trends continue.Screening for cancer
among people with diabetes is one measure that may prevent premature mortality from cancer in the future.
Expected future outcomes:
This project will allow a better and fuller assessment of the likely burden and consequences of diabetes,obesity,
and cancer as well as informing clinical practice about the appropriate care of diabetic and/or obese patients.
This may include routine screening of cancer among diabetes patients or patients attending obesity clinics.
Name of contact:
Dianna Magliano
Email/Phone no. of contact:
dianna.magliano@bakeridi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 112600
CIA Name: A/Pr Joanne Aitken
Admin Inst: Cancer Council Queensland
Main RFCD: Epidemiology
Total funding: $399,962
Start Year: 2000
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Melanoma diagnosis, and the effect of screening on depth of invasion of melanoma.Melanoma diagnosis, and
the effect of screening on depth of invasion of melanoma.
Lay Description (from application):
AIMS This study will assess how melanoma is diagnosed in Queensland, and if improvements can be made. It
will assess if skin screening gives earlier diagnosis of some melanomas, and also if it leads to the diagnosis of
some thin melanomas which would not progress if left alone. SIGNIFICANCE Melanoma is the most common
invasive cancer in Queensland, with some 1,963 people diagnosed annually with the disease. The outlook for
these patients varies dramatically with the depth of invasion of melanoma. Melanoma diagnosed and treated
when very thin has an excellent long-term outcome, whereas the outcome for deeply invasive melanoma is
much less favourable. Improvements to diagnosis are currently our best hope of reducing deaths and serious
distress from this disease. This will be the largest study in the world of the process of diagnosis of melanoma:
information on how melanoma presents, and the time between presentation and diagnosis will be compared
between thin and deeply invasive melanoma. Results may indicate areas for improvement in education or
health services. The use of screening, either by individuals themselves or by health professionals, has the
potential to achieve early diagnosis. However, there is currently no good information on whether screening is
actually effective. This study will assess the impact of self-screening and doctor screening on the depth of
invasion of melanoma at presentation, and ultimately on the likelihood of dying from melanoma. The study
will also assess the potential impact of screening on the over-diagnosis of lesions which while labeled as
melanoma, may in fact be biologically non-progressive. This is an important issue of current concern
internationally. This study will be one of only two studies in the world currently addressing this issue. This
project is directly relevant to the early detection and optimum management of the most common invasive
cancer in Queensland, and will have relevance internationally.
Research achievements (from final report):
This case control project began in January 2000 and subject recruitment and data collection was completed by
July 2004. The project's recruitment targets have been exceeded and analysis of results is currently underway., ,
Cases comprise 3,772 Queensland residents diagnosed with histologically confirmed first primary invasive
cutaneous melanoma between 1 January 2000 and 31 December 2003, aged 20-75 years. Cases were
ascertained through the Queensland Cancer Registry, with permission sought from their treating doctor before
contact was made with the patient. A total of 4,839 eligible patients were selected, doctors gave consent for
93.2%, and 86.1% of these cases agreed to participate, for an overall consent rate of 80.3%. , , Controls
comprised 3,824 residents randomly selected from the Queensland Electoral Roll during the same period. We
approached 7,594 controls and consent was obtained from 3,972 (52.1%). , , Our final dataset is unique in that
it consists of data at the population level examining the detection and diagnosis patterns of melanoma patients.
This will allow us to describe who is detecting melanoma, what doctors are consulted before definitive
diagnosis, the effects of any delays between detection and diagnosis and the factors associated with diagnosis
of thick melanoma. , , The dataset also consists of known risk factors for melanoma and both clinical and self
skin screening behaviours for these patients diagnosed with melanoma and for the matched control population.
This will enable us to assess whether skin screening is associated with earlier diagnosis and also whether
screening leads to the possible over-diagnosis of some early melanomas which otherwise may not progress., ,
Analysis of this data is currently underway and it is anticipated that these results will be published during 2005.
Expected future outcomes:
It is expected that a number of scientific publications will result from this project describing the detection and
diagnosis of melanoma, and the relationship between skin screening practices and melanoma prognosis. These
publications should inform policies regarding early detection and the practice of screening for melanoma.
NHMRC Research Achievements - SUMMARY
Name of contact:
A/Prof Joanne Aitken
Email/Phone no. of contact:
JAitken@qldcancer.com.au
NHMRC Research Achievements - SUMMARY
Grant ID: 339100
CIA Name: A/Pr Peter Baade
Admin Inst: Cancer Council Queensland
Main RFCD: Epidemiology
Total funding: $187,000
Start Year: 2005
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Investigating the utility of primary care skin cancer clinics in QueenslandInvestigating the utility of primary
care skin cancer clinics in Queensland
Lay Description (from application):
Skin cancer is the most common cancer in Australia, with an estimated 375,000 people being treated for some
skin cancer in Australia in 2002, and 1462 dying from the disease (mainly from melanoma) in 2001. Australia
has the highest rate of skin cancer, both melanoma and non-melanoma is the world. However, if detected early,
skin cancer is curable, and the focus of current treatment programs internationally is to detect the disease
before it progresses to an advanced stage. A large proportion of skin cancers are first detected by the nonmedical community. However, due to the two-tiered medical system in Australia, a person first seeks medical
opinion from a general practitioner (GP), who acts as a gatekeeper for further treatment from a specialist.
Therefore the ability of GPs to be able to discern which lesions require further treatment is crucial, both for the
patient, and the financial burden on the health system. A recent development has been the establishment of
dedicated "primary skin care clinics", which offer open access consultations to the community for the diagnosis
and treatment of skin cancers and pigmented lesions. The emergence of these clinics has created much debate
in the medical media. Concern has been expressed about the skills of practitioners in these clinics, whilst others
argue that sub-specialisation in primary care will lead to improvements in the management of patients. As there
is currently no data on the volume, casemix and diagnostic accuracy of these clinics it is difficult to assess the
diagnostic ability of skin cancer clinics. This will be the first project to quantify the role of skin clinics in the
diagnosis of skin cancer in the community, and in particular their case volume, casemix and diagnostic
accuracy, and assess these measures in relation to a comparable sample of general practitioners. Queensland is
an ideal location for a study of this type due to its high incidence of both types of skin cancer.
Research achievements (from final report):
Skin cancer is the most common cancer in Australia and the vast majority of cases are diagnosed and managed
within general practice. Recently Australia has witnessed the establishment of primary care skin cancer clinics
which offer open access consultations to the community for skin examinations and the diagnosis and treatment
of skin cancer. The emergence of these clinics has resulted in a great deal of debate primarily around issues
such as the skills of doctors working in these clinics. The aim of this project was examine the role that skin
clinics play in the diagnosis of skin cancer in the community., This project began in 2005 with recruitment of
primary care skin cancer clinics and general practitioners (GPs) in South-East Queensland. A total of 104 GPs
(response rate 54%) and 27 primary care skin cancer clinics (response rate 75%) representing 50 doctors,
participated in the study. The main aims of the study were to examine the types of suspicious skin lesions that
are presented to GPs and skin cancer clinic doctors, and to compare the diagnostic accuracy of the two groups
of doctors. , Participating doctors recorded details of over 28,000 patient consultations involving a skin
examination over the study period. On average GPs conducted approximately 7 skin examinations per week
and skin cancer clinic doctors around 85 examinations per week. In all, more than 11,000 suspicious skin
lesions were biopsied or excised. GPs excised or biopsied just over 3,000 skin lesions and skin cancer clinic
doctors nearly 8,000., Analysis of the data is now underway and will provide valuable information on how
doctors working in skin cancer clinics compare with GPs in relation to diagnosing skin cancer. The results of
this study will provide valuable directions about the most appropriate ways to detect skin cancer in our
community.
Expected future outcomes:
It is expected that a number of scientific publications will result from this study and these will be used as
background to formulating policies regarding how skin cancer is diagnosed in the Australian community.
NHMRC Research Achievements - SUMMARY
Name of contact:
Philippa Youl
Email/Phone no. of contact:
pipyoul@cancerqld.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 442301
CIA Name: Suzanne Steginga
Admin Inst: Cancer Council Queensland
Main RFCD: Health Counselling
Total funding: $307,407
Start Year: 2007
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Predicting and promoting improved long term adjustment for men with localised prostate cancer:
ProsCanPredicting and promoting improved long term adjustment for men with localised prostate cancer:
ProsCan
Lay Description (from application):
In the western world prostate cancer is the most common male cancer and the second most common cause of
cancer death. Currently, the most contentious public health issue regarding prostate cancer is uncertainty about
the benefits of diagnosing and treating prostate cancer at a localised stage. Prostate cancer is heterogeneous
and the risk of morbidity and mortality from localised disease is difficult to quantify owing to the cancer's
relatively slow growth rate. Thus, after the diagnosis of localised prostate cancer it is recommended that all
men be advised of three possible treatment options at a minimum: watchful waiting, radiation therapy, or
radical prostatectomy. Most men prefer active involvement in the treatment decision, however many find this
difficult due to uncertainty about the likely survival gain; significant treatment side effects and ambiguous risk
probabilities for these effects. While prostate cancer is common, mortality is low with most men surviving 10
years. This means quality of life after prostate cancer is a critical issue. Survivorship concerns for this patient
group include fears about cancer recurrence; managing physical effects of treatments; and social effects such as
disruption to daily living. Men seek help less for psychological difficulties than do women. Accessible and
well targeted support services for men are critical. This project aims to identify men who after the diagnosis of
localised prostate cancer are at risk of poorer psychosocial adjustment over the long term and to assess the
effectiveness of a psychosocial and decision support intervention in improving their long term outcomes.
Identification of predictors of men's adjustment over time and of effective ways to promote optimal long term
outcomes are important research questions that are as yet unanswered. The present research will be the first of
its kind internationally to address these questions.
Research achievements (from final report):
The Prostate Cancer Supportive Care and Patient Outcomes Project (ProsCan) trialled a tele-based psychoeducational intervention delivered by nurse counsellors to support men after prostate cancer diagnosis. A total
of 740 men participated in the randomised controlled trial, and men were followed up to 36 months postdiagnosis. This is the first randomised controlled trial to investigate the effectiveness of psychosocial
intervention in men with localised prostate cancer; include long term follow-up; and is the largest study
internationally of its kind. Results of the trial published recently (Chambers et al, 2012; see Final Report
Supplement Form for reference) indicate that sample heterogeneity plays an important role in the effectiveness
of the intervention. Younger men with higher education and income benefited the most from the program. This
highlights a critical future research question of how best to support men who have lower levels of education
and who may need alternative approaches tailored to their personal and social resources., The ProsCan project
also aims to inform knowledge regarding patterns of care and outcomes of men with localised prostate cancer,
and to investigate genetic markers of prostate cancer. ProsCan is the first study internationally to prospectively
assess long-term survivorship outcomes in a large cohort (1074 men) across a range of treatment and disease
states. Insight has been gained into the long-term impact of treatment outcomes on the psychosocial and quality
of life outcomes of men living with prostate cancer in Queensland. Geographic and socio-demographic
differences in pathways to care have provided valuable information for service planning and delivery. ProsCan
data is also being used to develop genetic biomarkers, and is part of an international consortium
(PRACTICAL) to investigate the genetics associated with prostate cancer.
Expected future outcomes:
Participants in ProsCan will be followed up annually up to 10 years post-treatment to assess the long-term
outcomes of men diagnosed with prostate cancer. Data collected from Medicare Australia and medical records
NHMRC Research Achievements - SUMMARY
will complement the data collected from questionnaires. Research will continue into the identification of genes
and development of genetic biomarkers.
Name of contact:
Suzanne Chambers
Email/Phone no. of contact:
suzanne.chambers@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 496001
CIA Name: Suzanne Steginga
Admin Inst: Cancer Council Queensland
Main RFCD: Health Counselling
Total funding: $601,331
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Randomised Controlled Trial of Early Intervention to Improve Sexual and Couple Functioning after Prostate
CancerRandomised Controlled Trial of Early Intervention to Improve Sexual and Couple Functioning after
Prostate Cancer
Lay Description (from application):
Treatment for localised prostate cancer has a long term negative impact on the sexuality and quality of life of
Australian men and their intimate partners. This study will trial a remote access couples based sexuality
intervention for this patient and carer group that has potential for broader translation.
Research achievements (from final report):
The ProsCan for Couples project, to our knowledge, is the first randomised controlled trial of peer support for
couples coping with prostate cancer, and the largest couples-based intervention trial for this patient group. The
trial has 189 couples enrolled, and has followed couples from treatment up to 12 months. Data is currently
being analysed, and will provide recommendations about the effectiveness of peer and nurse counselling to
support couples after prostate cancer; as well as providing an evidence-based sexuality intervention for men
with prostate cancer that can be rapidly translated into community and acute settings. Couples-based support
resources (including a DVD and guidebook) developed for this project will be made available to patients and
their families through existing services in Cancer Councils and national prostate cancer support networks.
Training materials developed for peers and nurses will be made available to other support organisations to
implement similar programs. A proposed collaboration with the University of Virginia (as part of the
Movember Australian Survivorship Action Partnership, if successful), aims to develop the program into a webbased resource, which will serve as an adjunct to the existing tele-based, audio-visual and print materials. This
will reduce the burden on regional and remote patients who currently need to travel to receive therapy and
support. The web-based intervention will be amenable to networking and linking into existing services, through
prostate cancer support groups, Cancer Councils and the national Cancer Helpline.
Expected future outcomes:
Follow up of couples will continue up to five years post-recruitment, to assess the longer term experiences of
couples after prostate cancer treatment. If funded, the web-based intervention will be developed and made
available to patients and their partners. Findings will be disseminated through conference presentations and
peer reviewed journal articles.
Name of contact:
Suzanne Chambers
Email/Phone no. of contact:
suzanne.chambers@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 561700
CIA Name: A/Pr Peter Baade
Admin Inst: Cancer Council Queensland
Main RFCD: Epidemiology
Total funding: $387,191
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Determinants of area-level inequalities in colorectal cancer survival: a multilevel studyDeterminants of arealevel inequalities in colorectal cancer survival: a multilevel study
Lay Description (from application):
Survival times for people diagnosed with colorectal cancer depend on where people live; typically lower in
rural and socio-economically disadvantaged areas. However we know very little about why these inequalities
exist. This study, the first of its type in Australia, examines how much of the survival inequalities are due to the
characteristics of individuals, and how much is due to the characteristics of the area itself. This will increase
our capacity to intervene to reduce these inequalities
Research achievements (from final report):
We have developed a database containing information about stage at diagnosis extracted from pathology forms
for over 30,000 Queenslanders diagnosed with colorectal cancer. Since stage at diagnosis is not routinely
collected by the Queensland Cancer Registry, this data extraction uniquely enabled us to separate the impact of
earlier diagnosis and improved treatment on the survival outcomes of people diagnosed with colorectal cancer
in Queensland., , We found evidence of a shorter survival time for Queenslanders with rectal cancer who live
relatively far from radiotherapy facilities, after adjustment for stage at diagnosis. The risk of cause-specific
mortality increased by 6% for each 100 km increment in distance from a hospital offering radiotherapy. , ,
Remoteness (survival lower in remote areas) and socio-economic characteristics (survival lower in
disadvantaged areas) of the area where a patient resides influence their survival after colorectal cancer
diagnosis independently of patient characteristics, , We conducted the first Australian studies to use multilevel
analysis to describe the relationship between breast cancer and colorectal cancer survival, geographic
remoteness, area disadvantage and individual-level socioeconomic status. Survival after a diagnosis of breast
cancer was lower in disadvantaged areas, independently of her individual-level characteristics., , These studies
provide important evidence to advocate for developing and implementing policy, cultural and clinical measures
to reduce the burden faced by rural and remote patients. It is also crucial to build on these results, by further
examining the underlying reasons for these observed inequalities be identified to appropriately target policies,
resources and effective intervention strategies. .
Expected future outcomes:
Using the foundation of existing work on this study to continue to investigate the impact of distance,
individual-level variables and area-level variables on diagnostic and survival outcomes for colorectal and
breast cancer.
Name of contact:
A/Prof Peter Baade
Email/Phone no. of contact:
peterbaade@cancerqld.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 265900
Start Year: 2004
CIA Name: Dr Patricia Livingston
End Year: 2006
Admin Inst: Cancer Council Victoria
Grant Type: NHMRC Project Grants
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $299,125
Title of research award:
Referral of men newly diagnosed with prostate cancer to a telephone-based support programReferral of men
newly diagnosed with prostate cancer to a telephone-based support program
Lay Description (from application):
Cancer diagnosis and treatments are stressors of major proportions. There is compelling evidence that
providing information, education and counselling services helps reduce emotional distress and improves
quality of life among newly-diagnosed cancer patients. The public health challenge for improving the
supportive care of cancer patients is to find a cost-effective way to deliver these services to this population.
Our response to this challenge is to test an innovative program that involves the cancer specialist referring
newly-diagnosed cancer patients to the Cancer Council Victoria's telephone information service staffed by
nurse counsellors, as an integral part of the patient's treatment management. The program involves the nurse
counsellor contacting patients and providing information and support at key times in the first six months after
diagnosis.
In this study, we will focus on prostate and male colorectal patients. The most common
registrable cancers in males are prostate and colorectal cancer; male cancer patients are a group known to
underutilise support services and among whom less research has been conducted on ways to improve
adjustment to a cancer diagnosis and treatment. If effective, this program could provide a way for supportive
care to be included among cancer patients, even those treated in rural centres, or where a multidisciplinary
team is not yet available.
Research achievements (from final report):
Telephone delivery of information and support to people with cancer is potentially a simple and cost-effective
approach that offers great advantages in terms of ease of access, greater reach of the patient population, and
anonymity for people diagnosed with cancer. The approach to deliver this service to patients tested in this study
is unique as it implicates the specialist into the process of recommending psychosocial care to new cancer
patients from diagnosis, and offers an out-call program to provide information and support during particularly
stressful periods. This study has shown that the call-back program is acceptable to its intended beneficiaries
and that its implementation in oncological practice is feasible.Moreover, this study contains valuable
information for health-care providers involved in the planning and implementation of interventions aimed at
improving access to services for men with cancer.
Expected future outcomes:
A referral and telephone follow-up by cancer nurses may be of greater benefit if concentrated on men who do
nothave psychosocial support, have many unmet information needs or have limited access to multi-disciplinary
care.
Name of contact:
Dr Trish Livingston
Email/Phone no. of contact:
trish.livingston@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 265902
CIA Name: Dr Suzanne Dobbinson
Admin Inst: Cancer Council Victoria
Main RFCD: Health Promotion
Total funding: $709,615
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
A randomised trial assessing a shade development intervention in secondary schools for adolescent skin cancer
preventionA randomised trial assessing a shade development intervention in secondary schools for adolescent
skin cancer prevention
Lay Description (from application):
Skin cancer is a significant burden to health costs, and morbidity and mortality in Australia. Reduction of
exposure to ultraviolet radiation (UVR) in sunlight, particularly during childhood and adolescence is an
important strategy for preventing skin cancer in later life. Adolescents have been particularly resistant to skin
cancer prevention messages. Despite a high knowledge of skin cancer, the majority of Australian adolescents
report a reliance on sunscreen, a resistance to hat wearing, and commonly experience sunburn, an important
indicator of increased risk of skin cancer. Psycho-social interventions have shown limited influence on
adolescents' sun protective behaviours to date. The current research proposal explores an alternative approach
to psycho-social interventions for adolescents. The study will assess the effect of increasing available shade at
secondary schools. In a randomised control trial study design, the change in the number of students using
certain outdoor areas at intervention schools will be observed 'before' and 'after' the installation of built shade
sail structures. Our main hypothesis states that the number of students using these newly shaded areas in
intervention schools will increase compared with use of equivalent unshaded areas in control schools. Shade
development is increasingly becoming an issue for secondary schools and given both the high cost of providing
shade structures and adolescents' resistance to other forms of sun protection it is important to establish that
adolescents will use this form of sun protection. This study will determine whether adolescents actively avoid
or seek shade and so provide evidence for informing decisions about further investment in shade provision in
schools.
Research achievements (from final report):
Despite good knowledge of skin cancer, Australian adolescents have been resistant to using sun protective
behaviours. Previously, education-only interventions were shown to be ineffective, while recent studies of
intensive education-based interventions have shown promise with younger adolescents in the United States.
However, increasing knowledge of skin cancer is unlikely to improve Australian adolescents' sun protection.
This research project sought to investigate whether an environmental strategy that did not rely on overcoming
barriers to peer image may be more appropriate. In a cluster-randomised trial we tested whether students would
use or avoid shaded areas in schools provided by newly installed purpose-built shade structures at study sites in
intervention schools compared with full sun areas at control schools. The study was conducted with all 51
schools recruited., We believe this is the first study to provide rigorous evidence that suggests that
environmental change alone can produce behavioural change for skin cancer prevention. The findings will be
particularly valuable in providing evidence for policy makers about decisions in investing in built-shade for
adolescents and schools in particular. This is important given the high cost of providing shade-structures and
adolescents' resistance to other forms of sun protection. In addition, this study has generated interest from top
researchers in skin cancer prevention, and development of a study proposal for a bi-national collaborative
research project is underway., The preliminary findings were presented at the 9th Behavioural Research in
Cancer Control conference in April 2008. Abstracts have also been accepted for presentation of the findings at
the Public Health Congress in Brisbane (July 2008) and at the American Public Health Meeting in San Diego
(October 2008). Following peer review of the findings we plan to disseminate the results more widely with the
support of the SunSmart program in Victoria.
Expected future outcomes:
A paper on the main findings of the trial was recently submitted to an international peer reviewed journal for
publication. , A second paper is underway examining whether specific factors, e.g. weather conditions or site
NHMRC Research Achievements - SUMMARY
features, maximised students' use of the shade-sails., The study findings will be disseminated to planners by
SunSmart Victoria.
Name of contact:
Suzanne Dobbinson
Email/Phone no. of contact:
Suzanne.Dobbinson@Cancervic.Org.Au
NHMRC Research Achievements - SUMMARY
Grant ID: 265903
CIA Name: Prof Ron Borland
Admin Inst: Cancer Council Victoria
Main RFCD: Health Promotion
Total funding: $752,250
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Supporting the Australian arm of the International Tobacco Policy Evaluation StudySupporting the Australian
arm of the International Tobacco Policy Evaluation Study
Lay Description (from application):
An international treaty, the Framework Convention on Tobaaco Control, is scheduled to be agreed on and
ratified over the coming year. This will provide huge impetus to the development and implementation of new
tobacco control policies. This project is part of a large international study designed to provide the best possible
scientific evaluation of tobacco control policies that are introduced in the participating countries. This project
will ensure that Australia continues to be one of the countries studied. This will maximise the benefits to
Austraia of the larger study, not only in providing quality scientific evaluations of the impact of new Australian
policies, but also providing evidence to assess the generalisability to Australia of policies adopted in other
participating countries . The study will help us understand how policies impact on smokers (their main target).
Tobacco policies may not achieve their aims because smokers may respond to them in unanticipated ways.
Understanding actual effects helps identify policies that work, and also helps to revise policies that fail (partly
or in full). It is at least as important to understand the impacts of policies that affect millions as it is to
understand interventions that only touch small numbers.
Research achievements (from final report):
This grant has complemented other grants to allow us to collect 5 annual waves of data in Australia and in the
other three comparison countries: UK, US and Canada. The research has helped demonstrate the benefits of
strong warning labels on tobacco products, the leading role Australia has played in the movement towards
smokefree places, and evidence of the importance of smoke-free public places in encouraging smokers to make
their own homes smokefree. We have demonstrated low levels of understanding among smokers about so
called "Light" cigarettes, which has provided support for moves to ban these terms worldwide. The research is
also advancing our understanding of the complexities involved in supporting smokers to quit. We have shown
more clearly that things that encourage smokers to quit are not the same as those things that help them stay
quit. We have shown that cutting down to quit is a less effective strategy than stopping abruptly. We are also
using the research to further our understanding of how smoking adds to social deprivation.
Expected future outcomes:
The findings from this project will help to guide policy makers in Australia and also around the world in
formulating evidence-based tobacco control policies that will have the greatest impact on smokers and smoking
cessation, thus enhancing the impact of the Framework Convention for Tobacco Control.
Name of contact:
Prof. Ron Borland
Email/Phone no. of contact:
ron.borland@cancervic.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 396405
Start Year: 2006
CIA Name: Prof Ron Borland
End Year: 2009
Admin Inst: Cancer Council Victoria
Grant Type: NHMRC Project Grants
Main RFCD: Health, Clinical and Counselling Psychology
Total funding: $922,582
Title of research award:
Maximising the effectiveness of interactive automated programs for smoking cessationMaximising the
effectiveness of interactive automated programs for smoking cessation
Lay Description (from application):
This project is to design, implement and trial automated programs to help smokers quit. It makes use of the
powers of modern computing and telecommunications. It uses information the person provides to personally
tailor advice and assistance to smokers as they progress from beginning to think about quitting through to being
a stable, happy non-smoker. In particular, we are interested in the relative value of detailed advice as compared
with the capacity of modern messaging technology (SMS, voice, images) to provide a set of prompts and
reminders that help smokers manage a quit attempt and help prevent them relapsing back to smoking. Once
we have developed the interventions, we will subject them to a rigorous scientific trial to see how effective
they are and also how cost-effective they prove. Our hope is that these programs will provide a cheap,
accessible and effective way of helping smokers to quit and thus help reduce the huge toll of smoking-related
disease.
Research achievements (from final report):
We have refined an existing program of Internet-based automated tailored advice for smoking cessation
(QuitCoach), and developed a program delivering text messaging support via mobile phone (Quit onQ). These
programs have the capacity to be used as stand-alone interventions, or used together as an integrated package
of support. The programs were developed with extensive input from smokers to ensure their acceptability and
usability, and several field trials were conducted in which detailed feedback was obtained. Following this
development process, a randomised trial was carried out to determine the efficacy of the intervention
components, both in isolation and as an integrated package. The trial also examined different ways of offering
the forms of support, to provide information on how to maximise uptake of tailored automated interventions in
the population., The trial has provided one of the first investigations of the potential of text messaging as a way
to deliver smoking cessation advice. The findings demonstrate that such programs can be effective both as a
stand alone intervention and as a complement to a more intensive program of tailored advice. The onQ program
is now being used by QuitSA as a stand alone intervention., The trial suggests a need to improve how the tools
we have developed are marketed to recent quitters, and to improve the capacity of the interventions to stimulate
quit attempts, as much of the benefit seems to be in preventing relapse.
Expected future outcomes:
The text messaging program is now being used by Quit SA, while the original QuitCoach continues to be used
widely. Quit Victoria are currently building the infrastructure that will enable the trial version of QuitCoach to
be implemented, complemented by Quit onQ and enhanced via improved integration with the Quitline.
Name of contact:
Prof Ron Borland
Email/Phone no. of contact:
Ron.Borland@cancervic.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 396407
CIA Name: Dr Gianluca Severi
Admin Inst: Cancer Council Victoria
Main RFCD: Epidemiology
Total funding: $348,656
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Predicting the Individual Risk of Prostate Cancer in Australian MenPredicting the Individual Risk of Prostate
Cancer in Australian Men
Lay Description (from application):
Prostate cancer is a major cause of disability and death in Australian men. A number of factors, particularly age
and family history, influence the risk of prostate cancer but, in contrast to breast cancer, we don't know what is
the risk of developing prostate cancer over a period of time for a man with a specific set of risk factors. In fact,
while a number of statistical models have been developed that use a woman's risk factor profile to estimate her
risk of breast cancer, none is currently available for prostate cancer. We will apply standard statistical methods
to existing data from the Australian Risk Factors for Prostate Cancer study and from the Australian Institute of
Health and Welfare to develop a prostate cancer risk prediction model. We will test how factor like age,
detailed family history, diet, baldness status and possibly previous PSA tests and prostate biopsies predict the
risk. After developing the model, we will test the accuracy of the predictions in three ways. First, using existing
data from the Australian Prostate Cancer Family Study, we will see whether the number of cases in a group of
men is close to the number predicted by the model (calibration). Second, to test whether the model discriminate
well men who develop prostate cancer from those who do not, we will collect family trees in a sample from
the Melbourne Collaborative Cohort Study. We will use these data also to estimate the optimal cut point: men
above this level of risk will be considered at high risk. Third, we will apply the model to existing data from the
Dutch Prostate Cancer Family Study (DPCFS) to test whether the optimal cut point identify high-risk men and
to validate the model in a non-Australian population. Finally, we will prepare a computer package that health
professionals will use as decision-making tool in different scenarios including individual cancer risk
assessment, design of prevention trials and targeting prevention programs to high-risk men.
Research achievements (from final report):
Prostate cancer is the most common cancer in Australia and a man's chance of being diagnosed with this
disease during his life is almost 10%. The risk of developing prostate cancer is not the same for all men and it
is modified by a number of factors including family history. We have developed a statistical model to predict
the risk of developing prostate cancer using data from Australian epidemiological studies and data from
Australian Cancer Registries and Mortality Registries. Using methods similar to those used by Gail for his
breast cancer risk prediction model, we predicted the risk of developing prostate cancer according to age and a
set of risk factors. The model shows that detailed family history alone can discriminate relatively well between
men who will develop the disease and men who will not. During this project we investigated various potential
risk factors for prostate cancer. In particular, we collaborated with colleagues in the U.K. to investigate genetic
variants associated with prostate cancer risk. This collaboration led to the identification of more than ten
variants associated with prostate cancer risk. Men carrying the risk allele in all of these variants have more than
three-fold increased risk compared with the general population. In the future we will extend the model to
incorporate genetic information. Our work forms the basis for a tool that will help identify men at increased
risk of prostate cancer.
Expected future outcomes:
As soon as new markers to identify aggressive prostate cancer are available we plan to develop a risk
prediction model specific for aggressive prostate cancer
Name of contact:
Gianluca Severi
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
gianluca.severi@cancervic.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 396408
Start Year: 2006
CIA Name: Dr Victoria White
End Year: 2008
Admin Inst: Cancer Council Victoria
Grant Type: NHMRC Project Grants
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $360,784
Title of research award:
DCIS management since publication of clinical practice recommendations: surgeons' practices and women's
experiencesDCIS management since publication of clinical practice recommendations: surgeons' practices and
women's experiences
Lay Description (from application):
Ductal Carcinoma in Situ of the breast (DCIS) now represents 15% of all new cases of breast cancer. Although
a benign disease, its diagnosis increases a woman's risk of developing invasive breast cancer and the goal of
treatment is prevention of invasive disease. However the characteristics that predict this progression have not
been clearly identified. Consequently women are confused about their diagnosis and both clinicians and
women are faced with complex treatment decisions. The National Breast Cancer Centre (NBCC) published a
set of eight clinical practice recommendations for the management of DCIS in September 2003 and a guide for
consumers in 2004. Currently there is no information regarding how the treatment recommendations have been
received by surgeons, the extent management of DCIS now follows these recommendations or the impact of
the treatment recommendations on the medical experiences of women with DCIS. This project will fill this gap.
The project aims to:
1. Examine the impact of clinical practice recommendations for the management of
Ductal Carcinoma in Situ (DCIS) of the breast on clinical practice 2. Determine awareness of and attitudes
towards the recommendations among surgeons treating DCIS and to examine the relationship between these
attitudes and clinical practice 3. Examine women's experience of a DCIS diagnosis, their understanding of its
prognosis and involvement in treatment decisions after release of a consumer guide in 2004 This research will
determine whether the publication of the treatment recommendations in 2003 influenced the medical care
women with DCIS recieve and identify the factors associated with surgeons and women that facilitate or
prevent the uptake of these recommendations. This information will be used to develop strategies increase
surgeons' adoption of the treatment recommendations in order to ensure that all women with DCIS have access
to the best care possible.
Research achievements (from final report):
We conducted surveys of the management of DCIS for all cases diagnosed in Victoria between 1/9/2002 to
31/8/2003 and 1/9/2006 to 21/8/2007 to examine change in clinical practice after the release of treatment
recommendation. We obtained data on 97% (n=342) of cases in 2002/3 and 98% (n=370) for 2006/7. Sixtythree surgeons (58% response) completed a survey on attitudes to the ATRs. Most treatment recommendations
were part of clinical practice prior to the recommendations release. More women treated by breast conserving
surgery were referred to a radiation oncologist in 2006/7 (67%) than 2002/3 (58%) and more received
radiotherapy in 2006/7 (53%) than 2002/3 (44%) in line with recommendations. While surgeons agreed with
most recommendations, items reflecting radiotherapy recommendations generated most disagreement. The
recommendations may have influenced use of adjuvant radiotherapy., , We also surveyed 231 women
diagnosed with DCIS between 1/9/2006 and 31/12/2007 about their treatment experiences. Most women had
not heard of DCIS before their diagnosis. Surgeons play a key role in surgical decisions and most women
receiving radiotherapy felt they had a choice about this. Women were generally satisfied with their
involvement in treatment decisions. Women understood that DCIS is a contained disease, can progress and that
treatment aims to prevent invasive cancer. 25% of the women were confused about the risk of developing
breast cancer or DCIS spreading. As DCIS is largely identified through mammographic screening, educational
resources could be generated to increase women's awareness of DCIS before diagnosis and for those
diagnosed, increase their understanding of its prognosis.
Expected future outcomes:
One paper has been accepted (available online) and another is being drafted. We expect both papers to be
published in the future
NHMRC Research Achievements - SUMMARY
Name of contact:
Victoria White
Email/Phone no. of contact:
vicki.white@cancervic.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400470
Start Year: 2006
CIA Name: Dr Robert MacInnis
End Year: 2012
Admin Inst: Cancer Council Victoria
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Population and Ecological Genetics
Total funding: $331,562
Title of research award:
Statistical models for genetic susceptibility to prostate and other common cancersStatistical models for genetic
susceptibility to prostate and other common cancers
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
Depeloped skills in genetic epidemiology, particularly modified segregation analysis and penetrance
analysesDeveloped a risk prediction model for prostate cancer that incorporates detailed family history and
common genetic variants Have begun work in developing a comprehensive risk prediction model for colorectal
cancerHave externally validated a risk prediction model for breast cancer (BOADICEA)Publication of 9
manuscripts in peer-reviewed medical journals (4 as 1st author, 2 as 2nd author)Chief investigator on grants
funded by National Institute of Health (USA), NHMRC, Victorian Breast Cancer Research Consortium and the
Cancer Council Victoria. Associate investigator on NHMRC Centre for Research Excellence for reducing the
burden of colorectal cancer PhD co-supervisor for Aung Ko Win, thesis title: "Cancer risks for people with
predisposing genetic mutations". He was a recent recipiant of the Premier's Award for medical research. On my
return to Australia, I have applied the skills that I have developed during my stay in Cambridge to various
different projects and have transferred much of the knowledge gained in the UK to other researchers at the
University of Melbourne and the Cancer Council Victoria.
Expected future outcomes:
Further publications will arise from this work. I will also submit for further funding in this area of research.
Mentoring and knowledge transfer to staff and PhD students on this topic will continue.
Name of contact:
Robert Macinnis
Email/Phone no. of contact:
macinnis@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 450104
CIA Name: Dr Gianluca Severi
Admin Inst: Cancer Council Victoria
Main RFCD: Epidemiology
Total funding: $798,907
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Markers of androgen action, genetic variation and prostate cancer riskMarkers of androgen action, genetic
variation and prostate cancer risk
Lay Description (from application):
This proposal aim to follow up evidence from a number of studies that genetic and non-genetic markers of
hormonal action in different periods of a man's life are associated with prostate cancer risk using a collection of
three large, independent epidemiologic studies on prostate cancer named the Prostate Cancer Program. A
principal objective is to collect exposure data on acne and digit ratio, and genotype cases and controls across
the studies of the Prostate Cancer Program for common genetic variants in 4 candidate genes in the hormonal
pathway. The established risk factors for prostate cancer are only age, race and family history. We anticipate
that this project will cast light on the role of hormones in prostate cancer and that we will identify new markers
of risk of prostate cancer and markers of disease aggressiveness. These outcomes will help us identifying men
who are at risk for prostate cancer to target screening and surveillance, and plan prevention strategies.
Furthermore, they will also form the basis for research on treatment targets.
Research achievements (from final report):
The causes of prostate cancer are poorly understood; age, a family history of prostate cancer, and ethnicity are
the only established risk factors. Finding the causes of prostate cancer, particularly aggressive prostate cancer,
is a priority to control and prevent this tumour. The hormonal pathway is widely considered to be important for
prostate cancer. The aim of this project was to investigate genetic and non-genetic markers of hormonal action
in different periods of a man's life and determine their association with prostate cancer risk using a collection of
three large, independent epidemiologic studies on prostate cancer named the Prostate Cancer Program., , In this
project we have found that:, 1) levels of sex hormones measured in adulthood are not associated with prostate
cancer risk, 2) a number of genetic loci linked to the hormonal pathway are associated with prostate cancer
risk, 3) male pattern baldness is associated with risk of early-onset prostate cancer, 4) the digit ratio, a marker
of in utero exposure to sex hormones, is not associated with prostate cancer risk, 5) circulating levels of P.
acnes antibodies is negatively associated with prostate cancer risk
Expected future outcomes:
Replication studies on the genetic loci we have identified are currently underway. Further studies will be
conducted to understand the causes of the associations that will be replicated.
Name of contact:
Gianluca Severi
Email/Phone no. of contact:
gianluca.severi@cancervic.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 504700
CIA Name: A/Pr Gianluca Severi
Admin Inst: Cancer Council Victoria
Main RFCD: Epidemiology
Total funding: $585,970
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Markers of inflammation and prostate cancer riskMarkers of inflammation and prostate cancer risk
Lay Description (from application):
It has been proposed that inflammation plays a major role in prostate cancer risk. We are well placed to test this
hypothesis following up evidence from our MCCS and RFPCS studies of associations between inflammatory
markers and prostate cancer risk. This proposed project may open for the first time opportunities for the
prevention of prostate cancer.
Research achievements (from final report):
In the first two years of the project we used more than 2,000 cases and controls from the Cancer Council
Victoria Prostate Cancer Program to perform an extensive work to identify common genetic markers of
susceptibility to prostate cancer (Petersen et al. Cancer Biomarkers Epidemiol Prev 2008; Tindall et al. BMC
Cancer 2010; Tindall et al. Carcinogenesis 2010; Tindall et al. The Prostate in press). In a collaboration with
Cancer Research UK we took advantage of novel technologies based on microarrays to search systematically
the genome and we identified several genetic variants clearly associated with prostate cancer risk (Eeles et al.
Nature Genet 2009; Kote-Jarai et al. 2011;Kote-Jarai et al. Hum Genet 2011;Al Olama et al. Nature Genet
2009). , In a study using data and blood samples from an existing case-control study of prostate cancer we
found a deacreased prostate cancer risk in men with evidence of a previous infection by a bacterium
(Propionibacterium acnes)(Severi et al. Brit J Cancer 2010). In a separate study using data from the Melbourne
Collaborative Cohort Study we found associations between a personal history of asthma and the use of drugs to
treat or prevent asthma are associated with prostate cancer risk (Severi et al. Cancer Epidemiol Biomarkers
Prev 2010). The meaning of these findings is still unclear and further work beyond this project will be required
to elucidate them., Another aim of this project was to identify inflammation markers of prostate cancer
aggressiveness using tissue samples. This work has led to the identification of three markers strongly
associated with death from prostate cancer. These results are going to be submitted for publication in mid2012.
Expected future outcomes:
The work on the genetic variants was recently expanded in a consortium funded by the European Union
including 50,000 cases and controls and resulted in the identification of several new genetic variants associated
with prostate cancer risk (paper submitted). The work on tissue samples will be further extended in order to
identify new prognostic markers and improve prediction of disease outcome.
Name of contact:
Gianluca Severi
Email/Phone no. of contact:
gianluca.severi@cancervic.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 504702
CIA Name: Prof Graham Giles
Admin Inst: Cancer Council Victoria
Main RFCD: Epidemiology
Total funding: $731,217
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Infections, inflammatory markers and prostate cancer riskInfections, inflammatory markers and prostate cancer
risk
Lay Description (from application):
Prostate cancer is the leading cancer for Australian men but apart from getting older and having a family
history of prostate cancer we do not know what causes it and nothing can be done to prevent it. This project
follows up recent suggestions that some prostate cancer might be due to infections by bacteria and viruses. We
will look for evidence of infection in blood samples and prostate tissue that we have collected from men with
prostate cancer and from controls without prostate cancer.
Research achievements (from final report):
Previous research had suggested that sexually transmitted infections might play a role in the development of
prostate cancer. However, the study found little evidence for the involvement of these infections, although it
did find that a type of bacteria (P. acnes) might be associated with decreased prostate cancer risk. The research
has identified a number of variants in genes responsible for inflammatory response to be associated with risk of
prostate cancer.
Expected future outcomes:
Work is ongoing in regard to genetic factors associated with prostatic inflammation which might be caused by
infections.
Name of contact:
Graham Giles
Email/Phone no. of contact:
graham.giles@cancervic.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 504708
CIA Name: Prof Dallas English
Admin Inst: Cancer Council Victoria
Main RFCD: Epidemiology
Total funding: $960,867
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Risk factors for gastro-oesophageal reflux disease and Barretts oesophagus in a prospective cohort studyRisk
factors for gastro-oesophageal reflux disease and Barretts oesophagus in a prospective cohort study
Lay Description (from application):
Heartburn caused by acid reflux is a common problem in Australia. In 2003, drugs used to treat disorders
caused by acid problems, such as heartburn, cost the PBS more than $500 million. Heartburn probably causes
a disease of the oesophagus called Barrett's oesophagus, which in turn is a cause of cancer of the oesophagus.
The aim of this study is to identify risk factors for heartburn and Barrett's oesophagus, so that we can find ways
to prevent them occurring.
Research achievements (from final report):
The study followed a cohort of men and women, aged 40-59 years at baseline, for 15 years. It was found that,
annually, 1% of cohort members experienced the initial onset of gastro-oesophageal reflux disease. Disease
onset was more common in women than men, was positively associated with waist circumference, was more
common in smokers and was less common in people who were physically active. Neither alcohol consumption
nor diet were associated with risk of onset of the disease, which contradicts many cross-sectional studies. This
suggests that the factors associated with the onset of reflux disease may differ from those that trigger episodes
of reflux.
Expected future outcomes:
We are presently analysing data on risk factors for gastro-oesophageal reflux disease and anticipate submitting
several articles for publication later this year. We also anticipate submitting several papers on risk factors for
Barrett's oesophagus later this year.
Name of contact:
Dallas English
Email/Phone no. of contact:
d.english@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 504711
CIA Name: Dr Laura Baglietto
Admin Inst: Cancer Council Victoria
Main RFCD: Epidemiology
Total funding: $294,462
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Risk and prognostic factors for breast cancer of different immunohistochemical subtypesRisk and prognostic
factors for breast cancer of different immunohistochemical subtypes
Lay Description (from application):
Breast cancer is a heterogeneous disease. Gene expression analysis has identified a number of subtypes that are
different with respect to pathology, prognosis, and response to treatment. Building on an existing cohort study,
we aim to identify risk and prognostic factors for molecular subtypes of breast cancer.
Research achievements (from final report):
Not all breast cancers are the same. In this study we looked at how lifestyle and other risk factors affect the
development of the different types of breast cancer. We also described the survival after diagnosis of the
women affected by the different types of breast cancer., We found that there is considerable variation in the
effect of the risk factors, depending on the type of breast cancer. A diet rich in fruit and salad might protect
against breast cancer, but its effect seemed to be stronger for one type of cancer. Obesity and having no
children increased the risk of one type of breast cancer only. We have also identified a number of genes that
slightly increased the risk of certain types of breast cancer., The breast cancer subtypes presented a lot of
variation also in term of survival.
Expected future outcomes:
The results of this research help to understand the causes of breast cancer and to identify cases with more
aggressive disease who might benefit from targetted intervention.
Name of contact:
Laura Baglietto
Email/Phone no. of contact:
laura.baglietto@cancervic.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 504715
CIA Name: Prof Graham Giles
Admin Inst: Cancer Council Victoria
Main RFCD: Epidemiology
Total funding: $1,017,664
Start Year: 2009
End Year: 2013
Grant Type: International Collaborations
Title of research award:
PRACTICAL AustraliaPRACTICAL Australia
Lay Description (from application):
0
Research achievements (from final report):
The Collaborative Oncological Gene-Environment Study (COGS) has been highly successful, having resulted
in five publications last year in Nature Genetics and eight in other high-impact journals; all 13 publications
were coordinated to be released at the same time as two commentaries on the study in Nature Genetics and a
dedicated website (www.nature.com/icogs) outlining and synthesising the outcomes reported in this first round
of publications. There had been 53 previously published loci associated with prostate cancer (P < 5 × 10-8).
Twenty-three new prostate cancer susceptibility loci were identified at genome-wide statistical significance
with overall prostate cancer risk (Table 1 in Nat. Genet. doi:10.1038/ng.2560, 27 March 2013). Thirteen SNPs
showed clear association when analysis was restricted to aggressive disease (significant at P < 0.01), and, for
22 of the 23 SNPs, the estimated odds ratio (OR) was in the same direction for aggressive and non-aggressive
disease. Aggressive disease was defined as that having Gleason score ? 8, prostate serum antigen (PSA) > 100
ng/ml, disease stage of distant (outside the pelvis) or death from prostate cancer. Fine mapping of a previously
reported locus at 5p15 identified multiple independently associated loci in the TERT region (Hum. Mol. Genet.
doi:10.1093/hmg/ddt086, 27 March 2013). This brings the total number of known susceptibility loci for
prostate cancer to 78. The public health implications and potential to use these findings for risk stratification
and screening are discussed in one of the aforementioned commentaries (see www.nature.com/icogs).
Expected future outcomes:
Work assessing gene-gene and gene-environment interactions is underway in collaboration with other
PRACTICAL investigators. The evidence to date suggests that established genetic risk factors are independent
and can be simply multiplied together in risk prediction models.
Name of contact:
Graham Giles
Email/Phone no. of contact:
graham.giles@cancervic.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 623208
CIA Name: Prof Dallas English
Admin Inst: Cancer Council Victoria
Main RFCD: Epidemiology
Total funding: $519,829
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Vitamin D and risk of cancer and mortality in the Melbourne Collaborative Cohort StudyVitamin D and risk of
cancer and mortality in the Melbourne Collaborative Cohort Study
Lay Description (from application):
Overseas studies indicate that vitamin D might protect against certain cancers and other diseases such as heart
disease and diabetes. Vitamin D is made when skin is exposed to sunlight. Because sunlight is stronger in
Australia than in most of the USA and Europe, where most studies were conducted, the results of those studies
might not be relevant to Australia. In this study, we will see if vitamin D is important for cancer and mortality
in Australia.
Research achievements (from final report):
We published a validation study of our novel technique to assess vitamin D status (concentration of 25OHD)
from archival dried blood spots publication. The measurements from dried blood spots predict plasma
concentrations exremely well and the measurements were very reliable., We also published our findings
regarding the variable distribution of 25OHD on blood spots and made recommendations regarding how such
samples should be accessed. , We found that risk of all cause mortality was inversely associated with 25OHD.
The association was strongest for people with pre-existing cardiovascular disease and diabetes, suggesting the
reverse causality due to these conditions partly explained the association. However, the association persisted
for participants who reported that they enjoyed good, very good or excellent health four years after their blood
was collected, suggesting that the association was not just due to people in poor health having low vitamin D
levels. We found no evidence that low vitamin D levels were associated with increased risk of breast cancer or
prostate cancer. There was little evidence that low vitamin D was associated with risk of colorectal cancer, but
it was associated with higher mortality from colorectal cancer. For the first time, we have shown that low
vitamin D status is associated with mortality in Australians. Because the association might not be causal, our
study shows the importance of conducting large-scale, population-based randomised controlled trials of
vitamin D supplementation.
Expected future outcomes:
We have manuscripts on death and risk of cancer about to be submitted for publication
Name of contact:
Dallas English
Email/Phone no. of contact:
d.english@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1011618
CIA Name: Dr Laura Baglietto
Admin Inst: Cancer Council Victoria
Main RFCD: Epidemiology
Total funding: $594,913
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Methylation as a risk and prognostic factor for breast cancerMethylation as a risk and prognostic factor for
breast cancer
Lay Description (from application):
DNA methylation is a process playing critical roles throughout life by altering the expression of genes. This
study aims to investigate the potential use of methylation as marker of risk and early diagnosis of breast cancer
in women with no clinical evidence of disease and marker of prognosis and response to treatment in breast
cancer cases.
Research achievements (from final report):
DNA methylation is a process playing critical roles throughout the life by altering the expression of genes. This
study investigated methylation as a potential marker of risk of breast cancer in women with no clinical
evidence of disease and marker of prognosis identifiable in tumour material. We have identified a large number
of methylation markers that appear to be associated with breast cancer risk that require validation in further
studies. we have also idnetified the methyltion can be used to subtype breast cancer and identify groups that
predict response to treatment.
Expected future outcomes:
We hope to validate the findings of this reserch in future studies and via collaboration.
Name of contact:
Prof Graham Giles
Email/Phone no. of contact:
graham.giles@cancervic.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1026892
CIA Name: Prof Melissa Southey
Admin Inst: Cancer Council Victoria
Main RFCD: Epidemiology
Total funding: $981,386
Start Year: 2012
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Methylation as a risk factor for prostate cancer.Methylation as a risk factor for prostate cancer.
Lay Description (from application):
DNA methylation is a process that plays a critical role throughout life by altering the expression of genes. We
aim to investigate the potential use of methylation as a target for prevention strategies and for men with no
clinical evidence of disease, as a marker of their risk for prostate cancer, particularly its aggressive form.
Research achievements (from final report):
The project has successfully prepared DNA representing the case and control groups for the methylation wide
analysis that was of high enough quality to run on the high density array. We established the in-house
methodology to apply the HM450K array assay that included the bisulfite conversion and the bead array assay.
We prepared 96 well plates of DNA arranged such that case and control pairs would run next to each other, on
the same chip, thus controlling for batch affects and reagent variation. We observed one serious issue with data
quality during the processing of the DNA plates. The Illumina SME reagent was identified as the cause of the
reduce data quality and illumina worked with us to understand the problem and to replace the necessary
reagents. In all, 7 plates of DNA (~672 DNAs) required re-assaying on the bead chip. We now have high
quality data for all the samples prepared for this project. Data analysis and interpretation is now well
progressed.
Expected future outcomes:
This project will be the foundation of work that identified methylation marks that are risk factors for prostate
cancer.
Name of contact:
Melissa Southey
Email/Phone no. of contact:
msouthey@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 117409
Start Year: 2000
CIA Name: Prof Peter Gunning
End Year: 2004
Admin Inst: Children's Medical Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $874,707
Title of research award:
Molecular Genetics of Cell and Tissue StructureMolecular Genetics of Cell and Tissue Structure
Lay Description (from application):
All cells have a characteristic shape (morphology), which is intrinsic to cellular function. A blood cell is
designed to move in a liquid medium whereas a muscle cell is optimised for physical movement of attached
bones. We are studying the mechanisms which control cell shape. We focus on the components of the cell
skeleton (cytoskeleton) which are implicated in the regulation of shape. In particular, we study the actin based
microfilament system. We have previously shown that two types of these components of the cytoskeleton are
able to control the structure of cells. In addition, we have found that variants of these two components (called
isoforms) are used to build structures in different parts of cells. This has led us to think about the anatomy of
cells and tissues in a new way. In some ways its like building a city. You create different kinds of buildings to
suit their purpose. Each building uses a combination of building blocks which suit the structural demands of
rooms and the overall building. In this study, we are proposing to dissect out genes, or parts of genes, which
supply specific types of building blocks. To do this, we plan to change these genes in mice and then examine
the impact on cell and tissue anatomy. This promises to contribute to the conversion of anatomical science and
pathology from descriptive to experimental/mechanistic disciplines.
Research achievements (from final report):
To establish that actin and tropomyosin isoforms are responsible for the regulation of cell and tissue structure
in an isoform specific manner. Conclusion, that actin and tropomyosin isoform sorting may regulate the
diversification of actin filament function at different intracellular sites (G10).
Expected future outcomes:
N/A
Name of contact:
Prof Peter Gunning
Email/Phone no. of contact:
peterg3@chw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 138102
Start Year: 2001
CIA Name: Prof Roger Reddel
End Year: 2003
Admin Inst: Children's Medical Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Oncology and Carcinogenesis
Total funding: $453,055
Title of research award:
Molecular Mechanisms and Control of Alternative Lengthening of TelomeresMolecular Mechanisms and
Control of Alternative Lengthening of Telomeres
Lay Description (from application):
Studies of a mechanism cancer cells use to protect the ends of their chromosomes The DNA within cell nuclei
is arranged in linear packages referred to as chromosomes, capped at each end by structures called telomeres.
Telomeres consist of a long stretch of a repetitive DNA sequence that does not contain any genes. Most
normal cells are unable to copy the DNA at the extreme ends of their chromosomes, so every time they divide
their telomeres get slightly shorter. This ultimately stops the cell from dividing any further, and acts as a very
potent barrier to the cell becoming cancerous. Some normal cells are not subject to this inexorable telomere
shortening: these are the germ cells in the testis and ovary, that are responsible for passing on genetic material
to the next generation. Such cells express an enzyme, telomerase, which is able to synthesise new telomeric
DNA to replace that lost during cell division. 85% of human cancers are also able to prevent shortening of
their telomeres - and thus have breached the barrier that normally prevents unlimited cell proliferation - via
telomerase activity. Therefore, if drugs that inhibit telomerase can be developed they may be a very useful new
form of cancer treatment. We have found, however, that some cancers are able to prevent telomere shortening
by a process that does not involve telomerase, and which we refer to as Alternative Lengthening of Telomeres
(ALT). One practical implication of this finding for the design of new cancer treatments is that telomerase
inhibitors will need to be used in combination with ALT inhibitors. In this study, we will determine A. how
normal cells keep the ALT mechanism permanently shut down and B. the molecular details of the ALT
mechanism itself. An understanding of these processes may ultimately contribute to the development of novel
cancer treatments that disrupt the ability of cancer cells to divide an unlimited number of times.
Research achievements (from final report):
Cellular immortality - the ability of cells to proliferate an unlimited number of times - is a key feature of cancer
cells. Our medium-term aim is to develop new cancer treatments that reverse immortalisation, and it has been
demonstrated in principle that this approach can render cancer cells non-malignant. In order for cells to become
immortal they need to prevent the shrinkage of chromosome ends (telomeres) that occurs every time a normal
cell proliferates. There are two ways cancer cells do this: (a) an enzyme, telomerase; and (b) a mechanism
called Alternative Lengthening of Telomeres (ALT). In this project we had two main aims: 1. to discover how
normal cells keep ALT switched off; and 2. to develop a rapid assay for ALT that will enable us to speed up
the search for genes required for ALT, and to permit testing of large numbers of compounds to find drugs that
inhibit ALT. While neither of these aims has been fully realised yet, the outcomes of these studies to date have
been as follows. 1. We confirmed the existence of ALT repressors by somatic cell hybridisation studies. We
discovered that a protein we investigated as a potential ALT repressor may facilitate telomerase activity; this
presents the possibility that the action of telomerase could be prevented by disrupting its interaction with this
protein. 2. We completed the preliminary experiments on which our assay system is based, and collaborated
with researchers in the UK to confirm the underlying hypothesis. In collaboration with researchers in France
and Italy, we investigated whether a new discovery about the behaviour of telomeres in ALT cells could be
used to develop a different ALT assay. We set up our assay as planned but the readout was found to be
insufficiently sensitive. We therefore started again to set up an assay based on the same principle but with a
different readout. We expect this will be completed in late 2004.
Expected future outcomes:
We expect that completion and validation of the assay system for ALT will speed up the process of detecting
genes or gene products that are involved in the ALT mechanism or are responsible for repressing ALT in
NHMRC Research Achievements - SUMMARY
normal cells. In addition, it will potentially form the basis of a high throughput screen for compounds that
inhibit ALT, as a step towards developing new anticancer drugs.
Name of contact:
Dr Roger Reddel
Email/Phone no. of contact:
rreddel@cmri.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 185204
Start Year: 2002
CIA Name: Prof Roger Reddel
End Year: 2004
Admin Inst: Children's Medical Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Oncology and Carcinogenesis
Total funding: $421,980
Title of research award:
Mechanisms of telomere cap functionMechanisms of telomere cap function
Lay Description (from application):
Title: Mechanisms of telomere cap function
DNA within each cell is packaged into chromosomes, the
ends of which are called telomeres. The DNA in telomeres consists of 6 letters of the genetic code, TTAGGG,
repeated hundreds or thousands of times. A number of proteins, including some that have not yet been
identified, bind to this DNA and form a cap structure to protect the chromosome ends. Telomeres need to be
able to serve a number of specialised functions, including protection against enzymes that degrade DNA ends,
and preventing chromosome ends from sticking to each other, while allowing access for DNA copying
enzymes when the cell is preparing to divide into two. In some inherited conditions, the telomeres fail to
perform these functions efficiently, leading to cellular dysfunction, premature ageing of cells, and ultimately
disease. In some types of cells, especially cancer cells, the telomeres also permit the access of molecular
machinery that lengthens the telomeres. There are at least two types of lengthening processes, one of which is
a complex enzyme called telomerase, and the other an incompletely characterised process that we discovered
and named Alternative Lengthening of Telomeres (ALT). In some circumstances, the telomeres of cancer cells
appear to be able to discriminate between telomerase and ALT, and to allow one mechanism to operate but not
the other. We will analyse how telomeres perform their capping functions, and will determine the differences
between normal and cancer cells in this regard. This will lay the groundwork for efforts to develop new forms
of cancer treatment that act by preventing cancer cells from lengthening their telomeres.
Research achievements (from final report):
Cancer cells can undergo limitless proliferation, due in part to their ability to prevent shortening of the ends of
their chromosomes (telomeres). Normal cells, in contrast, have a finite capacity for proliferation, and undergo
telomere shortening every time they divide. There are at least two mechanisms used by cancer cells to prevent
telomere shortening: an enzyme, telomerase, or a process called Alternative Lengthening of Telomeres (ALT).
Both of these mechanisms necessarily interact with telomeres and the macromolecular complex that protects
(or "caps") them. We studied the nature and function of this complex, and of the subnuclear structures (ALTassociated PML bodies [APBs]) that are unique to cells that use the ALT mechanism. We identified potential
novel components of the telomere complexes, at least one of which appears to be greatly enriched in cells that
use ALT. We achieved partial purification of APBs, and identified several previously unknown components of
these structures. We found that some telomerase-negative cells contain non-telomeric DNA within their
telomeres, and contain nuclear aggregates of telomere-related proteins that are distinct from APBs. This
discovery suggests the possibility that some telomerase-negative cancer cells use a previously unrecognised
ALT mechanism.
Expected future outcomes:
The continued growth of cancer cells is dependent on their ability to prevent telomere shortening. A detailed
understanding of the telomere cap will be critically important for designing new anti-cancer treatments that will
disrupt their telomere maintenance mechanisms.
Name of contact:
Roger Reddel
Email/Phone no. of contact:
rreddel@cmri.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 228412
Start Year: 2003
CIA Name: Dr Amanda Nouwens
End Year: 2006
Admin Inst: Children's Medical Research Institute Grant Type: Early Career Fellowships (Australia)
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $261,500
Title of research award:
Telomerase association with telomeres in human cell linesTelomerase association with telomeres in human cell
lines
Lay Description (from application):
Not Available
Research achievements (from final report):
Telomerase is an enzyme that is abundant in 85-90% of human cancers, and is necessary for the ability of the
cancer cells to divide indefinitely. Therefore finding ways to inhibit the action of telomerase is a promising
future therapy for cancer. In order to devise ways to block telomerase action, it is necessary to gain a greater
understanding of its biochemical means of action and its behaviour inside a cancer cell, subjects of which we
so far have only rudimentary knowledge. This project has resulted in several steps forward towards this
understanding. Firstly, we demonstrated that telomerase is a much rarer molecule in the cell than anticipated,
possibly the rarest. One particular subunit of telomerase, which was thought to be plentiful in non-cancerous
cells and hence of not much importance during cancer development, was also very rare in non-cancer cells,
indicating that regulation of this subunit also plays a role in cancer development. Secondly, we demonstrated
that this same subunit assembles into a large protein complex in cells that lack telomerase activity, implying
that it has a role of its own; future work will be directed at elucidating this role. Thirdly, we contributed to data
delineating the regions of the telomerase protein that interact with DNA, important fundamental information
about the enzyme.
Expected future outcomes:
All achievements listed above will be valuable for other researchers continuing the work into understanding
how telomerase works, which we hope will ultimately lead to new cancer treatments. We also developed and
fine-tuned research techniques during the course of this project that will enable more quantitative evaluation of
telomerase abundance.
Name of contact:
Assoc. Prof. Tracy Bryan
Email/Phone no. of contact:
tbryan@cmri.com.au
NHMRC Research Achievements - SUMMARY
Grant ID: 228413
Start Year: 2003
CIA Name: Dr Ying Cao
End Year: 2007
Admin Inst: Children's Medical Research Institute Grant Type: Early Career Fellowships (Australia)
Main RFCD: Not Allocated
Total funding: $278,625
Title of research award:
Identification and characterisation of telomere cap proteinsIdentification and characterisation of telomere cap
proteins
Lay Description (from application):
Not Available
Research achievements (from final report):
My fellowship has enabled me to carry out research to investigate the role of telomerase and telomere biology
in cancer. Telomerase is an enzyme which shows increased levels in more than 85% of human tumors.
Therefore telomerase is one of the most promising targets for new cancer therapies. The active human
telomerase is a complex composed of three components: hTERT, hTR and dyskerin. hTERT is the catalytic
reverse transcriptase, hTR serves as the RNA template for the addition of telomeric repeats, and dyskerin is an
RNA binding protein. hTERT has previously been generally believed to be the sole limiting factor for
telomerase activity. Therefore, hTERT has been the main focus of anti-telomerase drug development.
However, my research demonstrated direct evidence that hTR levels are also limiting for telomerase activity.
This further provides direct evidence that development of hTR inhibitors could also be promising for anticancer treatment.
Expected future outcomes:
The discovery of the limiting role of hTR in telomerase activity and telomere maintenance provides the
rationale for development of hTR inhibitors as anti-cancer drugs.
Name of contact:
Dr Ying Cao
Email/Phone no. of contact:
ycao@cmri.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 272503
Start Year: 2004
CIA Name: Prof Roger Reddel
End Year: 2007
Admin Inst: Children's Medical Research Institute Grant Type: Established Career Fellowships
Main RFCD: Oncology and Carcinogenesis
Total funding: $571,500
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
During this fellowship period, we continued investigating the molecular basis for immortalisation - the ability
of cancer cells to continue dividing an unlimited number of times. To be immortalised, cancer cells must
prevent the ends of their chromosomes (telomeres) from shortening, which they do by an enzyme, telomerase,
or a process we discovered previously called alternative lengthening of telomeres (ALT). 85% of cancers
depend on telomerase for their growth, and most of the remainder depend on ALT. We discovered the
molecular components of telomerase. This was published in the prestigious journal, Science, and lays the
foundation for determining the 3-dimensional structure of this enzyme and rational design of drugs to block its
activity, which we expect will be used to treat most cancers. We found that two of the three components are
present in cells in limiting quantities. With collaborators in Dunedin we found a cellular factor that increases
production of both these components. We discovered how cells prevent overlengthening of telomeres by
telomerase or ALT. We developed a test for detecting ALT in clinical tumour samples, and confirmed that
ALT is common in primary brain tumours and various types of sarcomas. We discovered new characteristics of
ALT cells, including a high level of recombination between telomeres (collaborating with scientists in Paris),
and altered methylation of subtelomeric regions (with collaborating scientists in Sydney). We discovered some
proteins that can switch ALT off; this may lead eventually to treatments for ALT-positive cancers.
Expected future outcomes:
Normal somatic cells have a limited proliferative capacity, whereas almost all cancers are immortalized.
Therefore, we are working towards the development of anticancer treatments that kill immortalised cells,
anticipating that these will be both effective and also have far fewer side effects on normal tissues than
currently available cancer chemotherapy.
Name of contact:
Roger Reddel
Email/Phone no. of contact:
rreddel@cmri.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 321708
Start Year: 2005
CIA Name: Prof Roger Reddel
End Year: 2007
Admin Inst: Children's Medical Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Genetics not elsewhere classified
Total funding: $471,000
Title of research award:
Detection of Alternative Lengthening of Telomeres in the MouseDetection of Alternative Lengthening of
Telomeres in the Mouse
Lay Description (from application):
In each cell, DNA is packaged into units called chromosomes, the ends of which (i.e., telomeres) become
slightly shorter every time they are replicated during the production of new cells. Continued cell replication
and hence continued telomere shortening eventually results in the inability of cells to replicate themselves any
further. Normal cells have mechanisms to slow down, but not completely prevent telomere shortening. The
development of a cancer depends on its cells being able to replicate themselves many times, and therefore they
need to find a method to prevent their telomeres shortening. We discovered one such method, called
Alternative Lengthening of Telomeres (ALT), that is used by some cancers. It has been shown in principle that
cancer cells can be killed by disrupting their ability to prevent telomere shortening. Therefore, in another
project we are developing methods needed to find drugs that inhibit ALT. In the meantime, we have found the
first evidence that some normal cells have an ALT-like mechanism. Our speculation is that cancer cells are
able to dysregulate and subvert this normal mechanism in order to prevent their telomeres from shortening. In
this project, we will analyse the ALT-like mechanism in mice, to determine its characteristics, and to determine
what tissues use it. This information will provide critically important insights into the ALT mechanism itself,
and the likely side effects of drugs that inhibit ALT.
Research achievements (from final report):
Whenever normal cells proliferate, the ends of their chromosomes (i.e., telomeres) shorten. When sufficient
telomere shortening has occurred, normal cell proliferation ceases. In contrast, cancers have unlimited cellular
proliferative capacity, and achieve this by acquiring a mechanism for telomere length maintenance. For this
purpose, about 10-15% of all human cancers use Alternative Lengthening of Telomeres (ALT). ALT is
particularly common in osteosarcomas (bone tumours), soft tissue sarcomas (such as liposarcomas), and
astrocytic brain tumours (including glioblastoma multiforme), but also occurs in carcinomas (e.g., ~8% of nonsmall cell lung cancers use ALT). Because the continued growth of cancer cells is dependent on their ability to
prevent telomere shortening. , This study has provided the first definitive evidence that ALT is also used to
some extent by normal cells. We do not know what purpose ALT serves in normal cells, but clearly it does not
prevent their telomeres from shortening and allow them to escape from the normal limits on cellular
proliferation.
Expected future outcomes:
The results of this study are a major step towards a more detailed understanding of the fundamental basis of the
ALT mechanism, and help lay the groundwork for the development of new anticancer treatments that target
ALT in the 10-15% of human cancers that depend on this mechanism.
Name of contact:
Professor Roger Reddel
Email/Phone no. of contact:
rreddel@cmri.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 321714
Start Year: 2005
CIA Name: Dr Alessandra Muntoni
End Year: 2008
Admin Inst: Children's Medical Research Institute Grant Type: Early Career Fellowships (Australia)
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $271,500
Title of research award:
Purification of ALT associated PML bodies (APBs) & identification of their protein components using a
proteomic approachPurification of ALT associated PML bodies (APBs) & identification of their protein
components using a proteomic approach
Lay Description (from application):
Not Available
Research achievements (from final report):
Brief introduction: Telomeres are the ends of linear chromosomes and are commonly regarded as a biological
clock for mammalian cells. They shorten with each round of cell division and, once they have reached a critical
length, prevent cells from dividing any further. A crucial feature of cancer cells is their ability to maintain their
telomeres long and to grow indefinitely, thus becoming immortal. Most commonly, cancer cells achieve
immortality by activating the enzyme telomerase, but about 10% of human tumours do so by activating a
mechanism named ALT (Alternative Lengthening of Telomeres). , Research achievements and significance: ,
The major aim of this project was to elucidate the molecular features of ALT: understanding how ALT is
regulated is a crucial step in developing treatments for cancers that use this mechanism. , We isolated and
analysed the DNA localized in ALT-Associated PML bodies (APBs), which are nuclear structures specifically
found in ALT cells. The size and structure of this DNA suggested that it is unlikely to be used for telomere
elongation in ALT cells. We therefore proposed that APBs are sites of storage for telomeric DNA rather than
active sites of telomere synthesis., We also studied the dynamics of DNA replication at the telomere of ALT
cells. We had previously described that ALT telomeres can elongate by copying DNA from other
chromosomes within the same cells. We now found that telomeres of ALT cells are also "self sufficient" in the
process of elongation, because they are able to fold back and copy their own DNA material.
Expected future outcomes:
We developed a method to obtain a cellular fraction which is highly enriched in APBs. Further improvements
to this technique could lead to purification of APBs and identification of proteins involved in ALT., We also
developed a reporter assay that can be optimised to screen for drugs that inhibit ALT.
Name of contact:
Alessandra Muntoni
Email/Phone no. of contact:
amuntoni@cmri.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 336704
Start Year: 2006
CIA Name: Dr Rose Boutros
End Year: 2010
Admin Inst: Children's Medical Research Institute Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $344,987
Title of research award:
Identification and functional analyses of novel post-translational modifications of CDC25B.Identification and
functional analyses of novel post-translational modifications of CDC25B.
Lay Description (from application):
Not Available
Research achievements (from final report):
This training fellowship allowed me to make significant contributions to the fields of cell cycle research and
cancer. During the first two years of the fellowship in the laboratory of Prof Bernard Ducommun in France, I
discovered that the CDC25B phosphatase, which activates CDK-cyclin complexes to regulate cell division,
plays an additional role in centrosome duplication and microtubule assembly. These processes are both
essential for normal cell division and are often misregulated in cancer. I also made the important observation
that a number of key cell cycle proteins localise asymmetrically to the centrosomes during cell division, the
significance of which is now under investigation by a number of other laboratories. This work resulted in 3 first
author publications, including a review paper in the high imapct journal Nature Reviews Cancer and 1 second
author publication. In the laboratory of A/Prof Brian Gabrielli at the Diamantina Institute, I produced a large
body of evidence to support a role for CDC25B in controlling the stability of the key centroosme protein
centrin-2, through its activity towards CDK2. This work resulted in 1 first and corresponding author
manuscript and another manuscript in preparation for submission to Oncogene. In the laboratory of Dr Megan
Chircop at the Children's Medical Research Institute in Sydney, I discovered that centrin-2 phosphorylation by
CDK-cyclins controls its nuclear-cytoplasmic trafficking and the role of centrin-2 in enhancing DNA damage
repair. This work has resulted in 1 first and corresponding author manuscript in preparation for submission to
Mol. Cell. Biol.
Expected future outcomes:
The centrosome is essential for normal chromosome segregation during cell division and is commonly
misregulated in almost all human cancers. Thus, understanding how key centrosome proteins are regulated will
provide us with a better understanding of how these processes, when aberrant, contribute to cancer initiation
and progression.
Name of contact:
Dr Rose Boutros
Email/Phone no. of contact:
rboutros@cmri.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 339471
Start Year: 2005
CIA Name: Dr Megan Fabbro
End Year: 2008
Admin Inst: Children's Medical Research Institute Grant Type: Early Career Fellowships (Australia)
Main RFCD: Oncology and Carcinogenesis
Total funding: $236,625
Title of research award:
Functional characterisation of a novel protein implicated in breast cancer progressionFunctional
characterisation of a novel protein implicated in breast cancer progression
Lay Description (from application):
Not Available
Research achievements (from final report):
Cytokinesis is the final stage of cell division that produces two daughter cells. Incorrect localisation and
modification of proteins that regulate this process cause cell division errors potentially leading to cancer. The
proposed project aimed to characterise how key cytokinesis proteins function to complete cell division
correctly. I identified a key centrosome protein, Cep55, as being involved in cytokinesis and characterised how
its modification by protein phosphorylation controls its function. Its role was determined to be during the
second phase of cytokinesis - membrane abscission. We subsequently identified the actin-binding and bundle
protein, EPLIN, as a Cep55 binding partner. However, unlike Cep55, we revealed that EPLIN function is
required for the first phase of cytokinesis, membrane ingression. Its role during this phase is to maintain the
localisation and sufficient amounts of key cleavage furrow components to the ingressing furrow. Further
investigation into the mechanisms required for the abscission phase confirmed that the endocytic protein,
dynamin II, is essential for cytokinesis. Like Cep55, dynamin II is modified by phosphorylation during cell
division and is required for the abscission phase to complete cytokinesis and generate two independent
daughter cells. Overall, these findings provide significant insight into the mechanisms that are required for
successful cell division to maintain genomic instability. This also constributes to our understanding of cancer
cell biology. Inhibitors towards many key mitotic proteins, such Aurora kinase, are currently in pre-clinical and
clinical trials for the treatment of cancer. Therefore, the biological significance of these discoveries is the
identification of potentially new drug targets, such as Cep55, EPLIN and dynII, to develop new
chemotherapeutic agents for the treatment of cancer.
Expected future outcomes:
We expect to identify additional proteins that functionally co-operate with Cep55 and dynII to successfully
complete cytokinesis. Thus, we will gain a better understanding of the mechanisms required for cell division.
We will also identify proteins that are suitable drug targets for the development of new chemotherapeutic
agents to improve cancer treatment.
Name of contact:
Megan Chircop (Nee Fabbro)
Email/Phone no. of contact:
mchircop@cmri.com.au
NHMRC Research Achievements - SUMMARY
Grant ID: 423405
Start Year: 2007
CIA Name: Prof Roger Reddel
End Year: 2009
Admin Inst: Children's Medical Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Oncology and Carcinogenesis
Total funding: $325,092
Title of research award:
Identification and characterisation of human telomerase holoenzyme componentsIdentification and
characterisation of human telomerase holoenzyme components
Lay Description (from application):
DNA is packaged into linear structures - chromosomes - that have two ends, called telomeres. When cells
proliferate, their telomeres normally shorten slightly, and this ultimately limits the number of times cells can
proliferate. This limitation is thought to contribute to ageing. Some tissues normally have a high rate of cell
turnover (for example in the bone marrow which is constantly producing large numbers of new blood cells),
and therefore a need for very extensive cellular proliferation. In these tissues, an enzyme called telomerase
slows down (but does not completely prevent) the rate of telomere shortening by replacing some of the DNA
that is lost as a result of proliferation. Telomerase is a complex enzyme with a number of subunits. In the past
few years, it has started to become clear that inherited deficiencies of some of these subunits cause diseases in
which cellular proliferation starts to fail at a young age. These patients typically die of bone marrow failure.
In contrast to conditions where there is telomerase deficiency, the great majority of cancers have
inappropriately high levels of telomerase activity which allow cancer cells to continue dividing without limit.
Telomerase is therefore regarded as a very promising target for new cancer treatments. In view of the
importance of telomerase to human health, it may seem very surprising that we do not yet know all of its
subunits. The reason for this is that, even in telomerase-positive cancer cells, the amount of telomerase present
is vanishingly small which has made it impossible so far to obtain sufficient quantities for even the most
sensitive analytical techniques. We are using very large numbers of human cells grown in a bioreactor, and
have devised a highly efficient method for purifying telomerase from them. We will analyse the purified
telomerase by contemporary mass spectroscopy techniques, identify all of the subunits, and characterise their
contribution to telomerase function.
Research achievements (from final report):
Telomerase is an RNA-protein enzyme complex that is present in ≥85% of all human cancers and is necessary
for the unlimited growth of cancer cells. In contrast, telomerase is undetectable in most healthy tissues.
Inhibition of telomerase activity with small-molecule drugs is considered a promising avenue for future anticancer therapies that should be applicable to a broad range of cancers and also display fewer side effects than
current chemotherapeutics., ,
The development of telomerase
inhibitors has been stymied by the lack of structural data for the telomerase enzyme and the inability to purify
the enzyme. At the onset of this research, the complete protein composition of the enzyme complex was still
unknown., ,
We developed a three-step
purification protocol that provided ~100,000,000-fold enrichment of telomerase. The final elution of the
enzyme was dependent on its ability to undergo catalysis, thereby ensuring that only catalytically active
enzyme complexes were obtained. The purified enzyme was analysed by mass spectrometry for unequivocal
protein identification. The composition of human telomerase was found to be surprisingly simple: Telomerase
Reverse Transcriptase (the catalytic protein component), Telomerase RNA, and the protein Dyskerin (an RNA
binding protein). To make up the observed size of the enzyme complex, we proposed that the complex contains
two copies of each of the three components., ,
The impact of these achievements
bears directly on structural studies of telomerase and eventual design of telomerase inhibitors: without knowing
the enzyme composition, and without the ability to purify the enzyme, structural studies are simply not
possible!
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
We are building on our achievements to determine the atomic X-ray crystal structure of the telomerase enzyme
complex. Our ability to purify large quantities of telomerase puts us in the unique position to pursue X-ray
crystallographic studies, which will then facilitate rational design of small-molecule inhibitors of telomerase.
Name of contact:
Dr. Scott Cohen
Email/Phone no. of contact:
scohen@cmri.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 477100
Start Year: 2008
CIA Name: Prof Phillip Robinson
End Year: 2012
Admin Inst: Children's Medical Research Institute Grant Type: NHMRC Research Fellowships
Main RFCD: Cell Neurochemistry
Total funding: $780,307
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a lab-based neurochemist-cell biologist with expertise in protein chemistry and pharmacology. My
research focuses on the dynamin family of proteins in the endocytosis of synaptic vesicles and in the molecular
mechanisms of synaptic transmission in th
Research achievements (from final report):
Our work over this 5 years has produced advances in two areas:Firstly, we made seminal contributions to
fundamental science in the research disciplines of neurochemistry, drug discovery, signal transduction and
phosphoproteomics. Our teams' research achievements on signal transduction and the endocytic proteins have
focused on mechanisms of synaptic transmission and on molecular mechanisms of mitosis. The common focus
was the dynamin (DynI, II and III) family of enzymes that are self-assembling molecular motors, which we
showed have multiple functions in the body including synaptic transmission, cancer and kidney function. We
have better defined the signalling mechanisms regulating diverse cellular and disease roles of the
dynamins.Secondly, our work has made transformational contributions to research through both
commercialisation and research translation. Together with the team Medicinal Chemist, Adam McCluskey, we
utilised the knowledge to develop new kinds of drugs targeting dynamin. Our discovery science sugessted to us
that if we could control the activity of dynamin in people we have the potential to develop new ways to treat
human disease. To this end we developed an extensive pharmacology around dynamin inhibtors and we
showed that they are novel and highly effective means to treat epilepsy brain cancer and infectious disease.
Expected future outcomes:
Our research will advance new basic science directions in the multiple function of endocytic proteins.
Imporantly we will capitalise on our drug discovery platform for proof-of-concept translation of the research
findings into potential new drugs.The goal will be to develop treatments for three untreatable diseases of
epilepsy, glioblastoma and kidney disease.
Name of contact:
Phillip J Robinson
Email/Phone no. of contact:
probinson@cmri.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 477102
Start Year: 2008
CIA Name: Prof Phillip Robinson
End Year: 2010
Admin Inst: Children's Medical Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $736,337
Title of research award:
The molecular mechanisms of abscission to complete cytokinesisThe molecular mechanisms of abscission to
complete cytokinesis
Lay Description (from application):
Cytokinesis is the final stage of cell division that produces two daughter cells. Incorrect localisation and
modification of proteins that regulate this process cause cell division errors potentially leading to cancer. This
project will characterise how key cytokinesis proteins function co-operatively to complete cytokinesis. This
research will increase our understanding of the cell division errors that contribute to cancer development,
ultimately identifying new targets for cancer therapy.
Research achievements (from final report):
Cell division (mitosis) is the process where cells separate into two daughter cells. This is highly regulated and
involves many gene products to produce two daughter cells which contain an equal amount of DNA. Incorrect
localisation and modification of specific proteins that regulate this process cause cell division errors, resulting
in genomic instability, which can increase the oncogenic potential. Our research has identified key proteins
involved in mitotic progression and we have characterised how these proteins function in this process. Our
current research projects are focused on understanding the network of specific proteins required for cell
division and how they co-operatively function to complete mitosis successfully. Thus, our research will enable
a better understanding of the error(s) that occur during cell division that contribute to cancer development. This
is critical to understand as these findings will ultimately identify new targets for cancer therapy. We have
developed and tested a range of drugs targeting one of these critical mitotic proteins and demonstrated that they
have anti-cancer properties. We are running a program to further perform preclinical testing of these drugs in
mouse models of cancer to reveal the most effective compound(s) that could be taken forward to human
clinical trials in the future.
Expected future outcomes:
An improved understanding of how endocytic proteins co-operatively function to successfully complete cell
division to generate two independent cells. This will identify new proteins that are potential anti-cancer drug
targets.
Name of contact:
Prof. Phil Robinson
Email/Phone no. of contact:
probinson@cmri.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 477104
Start Year: 2008
CIA Name: Dr Megan Chircop
End Year: 2011
Admin Inst: Children's Medical Research Institute Grant Type: Career Development Fellowships
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $380,559
Title of research award:
The molecular mechanisms of abscission to complete cytokinesisThe molecular mechanisms of abscission to
complete cytokinesis
Lay Description (from application):
Cytokinesis is the final stage of cell division that produces two daughter cells. Incorrect localisation and
modification of proteins that regulate this process cause cell division errors potentially leading to cancer. This
project will characterise how key cytokinesis proteins co-operatively function to complete cytokinesis. This
research will increase our understanding of the cell division errors that contribute to cancer development,
ultimately identifying new targets for cancer therapy.
Research achievements (from final report):
Cell division (mitosis) is the process where cells separate into two daughter cells. This is a highly regulated
process involving many gene products to produce two daughter cells which contain an equal amount of DNA.
Incorrect localisation and modification of specific proteins that regulate this process cause cell division errors,
resulting in genomic instability, which can increase the oncogenic potential. My research has identified key
proteins involved in mitotic progression and I have characterised how these proteins function in this process.
My current research projects are focused on understanding the network of specific proteins required for cell
division and how they co-operatively function to complete mitosis successfully. Thus, my research will enable
us to gain a better understanding of the error(s) that occur during cell division that contribute to cancer
development. This is critical to understand as these findings will ultimately identify new targets for cancer
therapy. We have developed and tested a range of drugs targeting one of these critical mitotic proteins and
demonstrated that they have anti-cancer properties. I lead a program to further perform preclinical testing of
these drugs in mouse models of cancer to reveal the most effective compound(s) that could be taken forward to
human clinical trials in the future.
Expected future outcomes:
An improved understanding of how endocytic proteins co-operatively function to successfully complete cell
division to generate two independent cells. This will identify new proteins that are potential anti-cancer drug
targets.
Name of contact:
Megan Chircop
Email/Phone no. of contact:
mchircop@cmri.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 477106
Start Year: 2008
CIA Name: Prof Roger Reddel
End Year: 2010
Admin Inst: Children's Medical Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Oncology and Carcinogenesis
Total funding: $398,157
Title of research award:
TRF2 protein and t-loop replication in Alternative Lengthening of TelomeresTRF2 protein and t-loop
replication in Alternative Lengthening of Telomeres
Lay Description (from application):
Telomere loss acts as a clock telling cells when to stop proliferating. Cancer cells ignore this clock and grow
indefinitely by preventing the normal loss of telomeres. Little is known about one of the methods cancers use
to preserve telomeres, called ALT, which is employed by some brain tumours and other cancers. We will
determine if the TRF2 protein is involved in controlling ALT. This will lay the basis for future anti-cancer
treatments targeted at ALT.
Research achievements (from final report):
Almost all human cancers avoid the normal barriers to unlimited cellular proliferation by activating a
molecular mechanism that prevents shortening of chromosome ends (i.e., telomeres) which accompanies
proliferation of normal cells. In approximately 10% of cancers, including some of the most aggressive and
most difficult-to-treat types, this is achieved by Alternative Lengthening of Telomeres (ALT). In this project,
we analysed the role of a telomere binding protein, TRF2, in ALT. TRF2 is known to be involved in formation
of telomere loops (t-loops), and we devised a novel assay which demonstrated for the first time that t-loops can
be the substrate for ALT-mediated telomere lengthening. However, the assay was not sufficiently quantitative
to determine whether TRF2 levels affected the amount of t-loop-mediated lengthening. TRF2 is also known to
be involved in suppression of DNA damage response at telomeres, and we found that ALT telomeres have a
very high level of DNA response foci and that these could be reduced by approximately 50% by artificially
increasing the level of TRF2 in the ALT cells. ALT cells have amounts of TRF2 that are similar to those in
non-ALT cells, but they have much more telomeric DNA, so we conclude that ALT telomeres have a relative
TRF2 deficiency that accounts for some of the characteristics of ALT cells and may contribute to the
mechanism. We have increased our understanding of what allows ALT to become activated in cancer cells, and
this may lay the foundation for designing cancer treatments that switch this mechanism off.
Expected future outcomes:
Further work is required to understand additional molecular details of the processes that allow ALT to be
activated in cancer cells. This may lay the foundation for designing cancer treatments that switch this
mechanism off.
Name of contact:
Professor Roger Reddel
Email/Phone no. of contact:
rreddel@cmri.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 631559
Start Year: 2010
CIA Name: Dr Rose Boutros
End Year: 2012
Admin Inst: Children's Medical Research Institute Grant Type: NHMRC Project Grants
Main RFCD: Cell Development, Proliferation and Death
Total funding: $495,011
Title of research award:
Centrosome overduplication contributes to tumorigenesisCentrosome overduplication contributes to
tumorigenesis
Lay Description (from application):
Cancer can be simplistically thought of as a disease of cell growth and division. In order to improve current
treatment regimes and identify new ones, the underlying mechanisms controlling cell proliferation need to be
fully understood. By defining these regulatory mechanisms, targets for current chemotherapeutic agents can be
further characterised and new ones identified. This will lead to the targeted developments of new classes of
drugs which can be used in the fight against cancer.
Research achievements (from final report):
We made remarkable progress with this grant, which will eventuate in 4 publications by the end of 2013.We
have investigated how the centrosome, an organelle found in all cells that is essential for normal cell division,
is regulated by protein modifications. Protein modifications, termed phosphorylation, function as an on/off
switch, to control how proteins behave. We investigated how phosphorylation regulates 2 key centrosome
proteins centrin 2 (cnt2) and gamma-tubulin (gtub). We derived mutants for both cnt2 and gtub that either
mimicked phosphorylation or were phospho-deficient and investigated their effects on centrosome structure
and function. In the case of cnt2, we found that phosphorylation had no obvious effect on the centrosomal
levels or function of cnt2. However, unexpectedly, we that phsophorylation controls the intracellular trafficking
of cnt2 between the nucleus and cytoplasm and that this trafficking of cnt2 is highly regulated by a number of
different mechanisms. This is most likely to be important for cnt2's secondary role in the response to DNA
damage. In the case of gtub, we found that phosphorylation controls the overall level of gtub protein that
accumulates at the centrosome. Given that the key role of gtub is to assemble the cell's cytoskeleton, altered
levels of gtub at the centrosome has significant consequences for cytoskeleton assembly and the completion of
mitosis, the final stage of cell division. Given that current anti-cancer treatments are aimed at disrupting the
cell cytoskeleton and cell division, we anticipate that these findings will aid in the development of more
specific anti-cancer agents in future studies.
Expected future outcomes:
Current anti-cancer therapies function by disrupting the cell cytoskeleton and/or cell division. Given that the
centrosome is essential for normal cell division, understanding how centrosome proteins including gtub, are
modified, will allow us to develop more effective drugs that specifically target actively dividing cancer cells
without harming normal cells, thus reducing toxic side-effects.
Name of contact:
Rose Boutros
Email/Phone no. of contact:
rboutros@cmri.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 593505
Start Year: 2010
CIA Name: Prof Carlene Wilson
End Year: 2012
Admin Inst: CSIRO Division of Human Nutrition Grant Type: NHMRC Project Grants
Main RFCD: Preventive Medicine
Total funding: $480,231
Title of research award:
Population testing of an internet-based Personalised Decision Support system for Colorectal Cancer
screeningPopulation testing of an internet-based Personalised Decision Support system for Colorectal Cancer
screening
Lay Description (from application):
This study will determine the impact of a fully developed computerised Personalised Decision Support (PDS)
package on colorectal cancer screening participation. The PDS tool is designed to guide people through the
decision processes relevant to deciding whether to undertake screening. The PDS presents personally tailored
messages aimed at progressing individuals towards screening test use and has the potential to supplement
traditional paper methods of increasing screening participation.
Research achievements (from final report):
This study established that access to information about the individual risk of colorectal cancer, the importance
and effectiveness of screening and the extent to which screening is socially endorsed, delivered online, leads to
significant changes on those psychological variables likely to impact of screening intention and screening
behaviour. However, tailoring information to individual differences does not appear to assist further. Webbased delivery, both tailored and untailored, resulted in 5 to 6% higher participation rates than mailed material.
Expected future outcomes:
This information will assist the development of web-based decision support materials for use by both NGOs
and the government.
Name of contact:
Carlene Wilson
Email/Phone no. of contact:
Carlene.Wilson@csiro.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1017078
Start Year: 2011
CIA Name: Dr Leah Cosgrove
End Year: 2013
Admin Inst: CSIRO Division of Human Nutrition Grant Type: NHMRC Development Grants
Main RFCD: Cancer Diagnosis
Total funding: $556,713
Title of research award:
Validation of a multiplexed blood based screening assay for the diagnosis of colorectal cancerValidation of a
multiplexed blood based screening assay for the diagnosis of colorectal cancer
Lay Description (from application):
Colorectal cancer (CRC) is the second most common cancer in Australia with poor patient outcome due to late
detection of the disease. We have developed a simple blood based test that can diagnose individuals with CRC
at an early stage when the chance of cure is greater than 80%.
Research achievements (from final report):
o
Colorectal cancer (CRC) is the
second most common internal cancer in Australia and the second leading cause of cancer death. Unfortunately,
30-50% of patients identified have tumours that have spread (metastasised) and their prognosis is very poor
with a five year survival of less than 10%. By contrast, greater than 90% of patients who present while the
tumour is still localised (Dukes' stage A) will still be alive after 5 years and can be considered cured. The early
detection of CRC and clinically significant pre-cancerous lesions (adenomas) would therefore significantly
reduce the health burden of this disease. , o
This NHMRC Development grant
has enabled us to identify and validate a unique panel of 3 protein based proteins that can accurately identify
individuals who have colorectal cancer. , o
We have made our own reagents so
we have greater assurance to the accuracy of the test. , o
As this is a simple blood test, this
will provide a more acceptable screening procedure than the current test faecal occult bowel test resulting in
greater participation rates of screening. , o
This test will save lives and reduce
health costs by its greater ability to pick up earlier stage disease when the patient could be cured by surgery.
Expected future outcomes:
o
A blood test will save lives by
increasing screening participation and a greater ability to detect early stage disease thereby potentially curing
the individual., o
Useful in triaging patients to
determine the need and urgency of having further tests e.g: colonoscopy, thereby reducing health costs and
trauma.
Name of contact:
Dr Leah Cosgrove
Email/Phone no. of contact:
leah.cosgrove@csiro.au
NHMRC Research Achievements - SUMMARY
Grant ID: 353511
CIA Name: Prof James Semmens
Admin Inst: Curtin University of Technology
Main RFCD: Epidemiology
Total funding: $583,500
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
The WA Safety and Quality of Surgical Care Project: Improving the Safety, Quality and Provision of Surgical
Care.The WA Safety and Quality of Surgical Care Project: Improving the Safety, Quality and Provision of
Surgical Care.
Lay Description (from application):
The basis of this application is a three-year project which aims to improve the safety, quality and the provision
of surgical care. This application constitutes the core of the WA Safety and Quality of Surgical Care Project
(SQSCP), which was established in 1996 to evaluate the clinical epidemiology, health care utilisation, patient
safety and health outcomes following admission to hospital for specific surgical and medical procedures in
Western Australia (WA). The study will use data from the WA Data Linkage System, which brings together 15
million records from hospital morbidity, death, cancer, midwives notification and mental health databases.
Surgical procedures have been selected for review based on national priorities and after consultation with the
WA Branch of the Royal Australasian College of Surgeons (RACS) and other clinical Colleges. This
application proposes to continue the core research activities of the SQSCP. A special focus will be on the use
of minimally invasive surgical techniques including laparoscopic, endoscopic and endoluminal procedures,
which have increased dramatically during the last decade. The study will also evaluate differences in the
outcomes of surgical care in rural and metropolitan settings. The findings of the SQSCP will be
comprehensively disseminated to surgeons, the RACS, hospital managers, health policy makers and
consumers.The rationale of this project is that by providing high quality data on the epidemiology, utilisation
and outcomes of surgical care, we will be able to increase the knowledge-base that will contribute to
improvements in the safety, quality and provision of surgical care in Australia and internationally. The aims of
the SQSCP are consistent with national health priorities and the recommendations of the Taskforce on Quality
of Australian Health Care Study, the Australian Council for Safety and Quality in Health Care and the National
Institute of Clinical Studies.
Research achievements (from final report):
The SQSCP used data from the WA Data Linkage System, supplemented by additional information from chart
review where appropriate, to evaluate the clinical epidemiology, utilisation and outcomes of a broad scope of
selected procedures. Each procedural involved surgeons as part of the evaluation team. The total research
output of the SQSCP since 1996 is 158 scientific papers, of which 37 papers and 3 book chapters were
published as a result of this grant. Of particular importance were open and endoluminal repair of abdominal
aortic aneurysm including the use of fenestrated grafts, wide bodied stent grafts to treat iliac disease; peripheral
artery disease; laparoscopic technology evaluation, hysterectomy, breast cancer management and treatment;
cataract surgery; the locational and social inequalities of procedural care, and the evaluation of laparoscopic
cholecystectomy and other endoscopic procedures. For these procedures we established benchmark standards
of performance, guidelines for treatment, assessed difference in outcomes between metropolitan and rural
patients, and assessed patient outcomes including the risk of adverse events. The outcomes were widely
disseminated to surgeons, the RACS, health care managers and policy makers, and consumers. We provided a
focus on translational research to change clinical practice and influence health policy. As a result of this work,
two of the CIs received national awards, CIA Semmens the RACS medal and CIC Lawrence-Brown an Order
of Australia. Continued funding was approved by the NHMRC for the SQSCP for 2008-2010 (#479205)
Expected future outcomes:
The future outcomes will include the provision of evidence based data to influence the guidelines and treatment
for patients requiring surgical care. The data will contribute to changes in safety and quality of surgical
practice, support health policy and influence the development of models of care.
NHMRC Research Achievements - SUMMARY
Name of contact:
Professor James Semmens
Email/Phone no. of contact:
James.Semmens@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 425505
CIA Name: Prof Robert Donovan
Admin Inst: Curtin University of Technology
Main RFCD: Preventive Medicine
Total funding: $592,838
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
A longitudinal investigation of the efficacy of pharmacological smoking cessation aids in real-life settingsA
longitudinal investigation of the efficacy of pharmacological smoking cessation aids in real-life settings
Lay Description (from application):
Currently around 3 million Australians, or 17% of people aged 14 years and over, smoke tobacco daily. These
smokers are at major risk of developing coronary heart disease, stroke, peripheral vascular disease, and a
variety of cancers, including lung, laryngeal, oral, kidney, bladder, breast, pancreas and colon cancers. At any
one time almost half of Australian smokers intend to quit smoking or have already set a date to do so but few
(around 10%) succeed on each attempt. Clinical trials of quitting aids, such as nicotine patches, gum and
Zyban, suggest that smokers are around twice as likely to quit if using these. However clinical trials are
conducted in artificial environments and these quitting aids appear to have a far smaller impact on successful
quitting rates in the 'real world'. Pharmaceutical quitting aids are heavily advertised by drug companies and
widely used in Australia. Futhermore the Commonwealth Government has invested over $133 million dollars
subsidising such aids to Australian smokers in the past four years. However it is not known to what extent these
quitting aids have made a difference to Australian smoking rates. Sales volumes of pharmaceutical quitting aids
appear not to have translated into expected increases in numbers of smokers successfully quitting, suggesting
they are less effective than clinical trials suggest. The present study aims to investigate whether pharmaceutical
quitting aids actually are less effective in the 'real world', and if so, why.
Research achievements (from final report):
A sample of 1204 Western Austrlian smokers participated in one survey every three months over 9 consecutive
occasions to ask about any quit attempts and changes to their smoking habits. Half (49.8%) of the participants
made at least one quit attempt during the two year period and 24% successfully quit. We recorded their
incidental use of cessation pharmaceuticals and concluded that the efficacy of such in real-life situations is far
different than in randomised, placebo-controlled trials. We conclude that the efficacy of NRTs and Zyban may
be exagerated. For instance, nicotine replacement therapies conferred a 46% increased chance of remaining
abstinent at 6 months compared to no assistance but no difference was observed at 12 months. This contradicts
the established literature which suggests smokers are twice as likely to quit. Our results highlight the
limitations of relying upon double-blinded placebo trials to test cessation pharamceuticals trying to ween drug
addicts away from their drug of choice, and that comparison trials would be more appropriate.
Expected future outcomes:
A number of papers are currently being prepared for publication in peer-reviewed scientific journals covering
the areas of: the efficacy of cessation pharmaceuticals in real-life settings; the modern reasons smokers credit
for prompting quit attempts; and the relative adoption of cessation pharmaceuticals by SES.
Name of contact:
Professor Rob Donovan
Email/Phone no. of contact:
r.donovan@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 479236
CIA Name: Dr Georgia Halkett
Admin Inst: Curtin University of Technology
Main RFCD: Clinical Chemistry
Total funding: $50,000
Start Year: 2009
End Year: 2010
Grant Type: SRDC - Research
Title of research award:
Primary care: what is their approach to patients with advanced cancer and those who require
radiotherapyPrimary care: what is their approach to patients with advanced cancer and those who require
radiotherapy
Lay Description (from application):
It is recommended that 50-60% of all cancer patients receive radiotherapy at some time in their disease.
However, only 38% of all cancer patients receive radiotherapy in Australia. Advanced cancer patients may be
missing out on radiotherapy because they are not referred for palliative radiotherapy. The specific aims of this
study are to: Explore the primary care approach to patients with advanced cancer and particularly those who
require radiotherapy; Define factors that influence how Australian GPs respond to symptoms of advanced
cancer; Map the patients’ perspective on current referral practice for palliative care. This project will be
comprised of three stages: simulated consultations with GPs, survey of GPs and patient interviews. These
methods will enable researchers to develop an understanding of the primary care approach to patients with
advanced cancer and those who require radiotherapy and how patients with advanced disease are referred for
treatment.
Research achievements (from final report):
, The aims of this study were to:, 1. Explore the primary care approach to patients with advanced cancer and
those who require radiotherapy, 2. Define factors that influence how GPs respond to symptoms of advanced
cancer , 3. Map the patient's perspective on current referral practice for palliative care., Three research methods
were used: Simulated Consultations with GPs, National GP survey using vignette scenarios and Patient
interviews. , Analysis of the simulated consultations suggests that GPs have varying knowledge of radiotherapy
and are currently not referring all palliative patients appropriately. We can identify which cases GPs managed
well and what aspects of the cases GPs did not manage appropriately. , Analysis of the survey data also
identified that GPs had varying knowledge and would not always refer appropriately. We can identify
circumstances and factors that reduce the likelihood of GPs referring advanced cancer patients for palliative
care and radiotherapy. , Finally, interviews with patients identified that not all relationships between GPs and
patients are helpful with regard to palliative care and appropriate referral. GPs have varying levels of
involvement with patients following an advanced cancer diagnosis. We are able to provide a summary of the
factors that are likely to help, hinder or make a difference to GP involvement in shared cancer care and
appropriate referral.
Expected future outcomes:
The results of this study will be shared with specialists and GPs to assist them in developing improved shared
cancer care models for patients with advanced cancer. We intend to use the results of this study to develop
education for GPs. We will also develop a referral package on palliative care and radiotherapy to assist GPs
with appropriate referral. , Three manuscript in preparation. ,
Name of contact:
Dr Georgia Halkett
Email/Phone no. of contact:
g.halkett@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 513761
CIA Name: Prof John Olynyk
Admin Inst: Curtin University of Technology
Main RFCD: Gastroenterology
Total funding: $428,496
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Research Fellowships
Title of research award:
Practitioner FellowshipPractitioner Fellowship
Lay Description (from application):
I am a Gastroenterologist who has established major research programs in the broad areas of the pathogenesis
of Hereditary Haemochromatosis, the role of hepatic stem cells in the pathogenesis of liver cancer and
colorectal cancer screening.
Research achievements (from final report):
I have translated research into policy and practice for the following organisations: Health Department of WA
(Patient Blood Management Program, Colonoscopy Model of Care, Evaluation of new therapies for anaemia),
Australian Red Cross Blood Service (New national pathway for provision of therapeutic phlebotomy of
Hereditary Haemochromatosis subjects in Australia) and Murdoch University (Exjade and hepcidin assays for
research trials). I have trained postgraduate research students and Gastroenterologists. I have successfully
received NH&MRC project grant funding and pubilshed over 160 peer reviewed original publications.
Expected future outcomes:
Continued translation of research into clinical practice and policy. Continued publication, receipt of research
grants from funding agencies and industry and continued impact on my clinical discipline.
Name of contact:
Julie Coutts
Email/Phone no. of contact:
j.coutts@murdoch.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1067331
Start Year: 2014
CIA Name: Prof Lorna Rosenwax
End Year: 2016
Admin Inst: Curtin University of Technology
Grant Type: NHMRC Project Grants
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $364,936
Title of research award:
Reducing demand on emergency departments in the last year of lifeReducing demand on emergency
departments in the last year of life
Lay Description (from application):
People in their last year of life who attend emergency departments (EDs) could often be better cared for
elsewhere. Our severely overcrowded EDs, and the staff who work in them, are poorly equipped to provide
appropriate end-of-life care. This research describes how people in their last year of life use EDs, the impact of
this use upon ED services and how the provision of adequate primary care and supportive care services in the
community care may be a more appropriate and economically viable option for people at the end-of-life.
Research achievements (from final report):
The significance of the Dementia Seeding Grant is the project now has progressed through the lengthy process
of acquiring the data from six different databases, data linkage has occurred, ethical approval has been
obtained, cleaning the data has progressed and analysis has commenced. The data was sourced from six
databases within the Data Linkage System in Western Australia.
Expected future outcomes:
Greater understanding of health service use in the last year of life for people with dementia.
Name of contact:
Professor Lorna Rosenwax
Email/Phone no. of contact:
l.rosenwax@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 479505
CIA Name: Prof Wei Duan
Admin Inst: Deakin University
Main RFCD: Surgery
Total funding: $445,097
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
A novel tumour-targeting nanoliposome drug delivery system for the treatment of malignant gliomasA novel
tumour-targeting nanoliposome drug delivery system for the treatment of malignant gliomas
Lay Description (from application):
Most patients with malignant brain tumours die within a year after diagnosis due to the difficulty in effectively
delivering drugs to the tumour cells. We aim to develop a safe and novel drug delivery system to effectively
deliver anticancer drugs and novel anticancer agents to brain tumour cells that remain in normal brain after
surgery. The success of this project will bring us a step forward in our efforts to significantly improve the
survival rate and quality of life of such patients.
Research achievements (from final report):
We have developed a totally human-compatible and human-degradable nanoliposome nanocarrier.
Comprehensive pharmacokinetics and biodistribution studies on the in vivo behaviour of our nanoliposomes
have revealed that newly developed nanoliposomes have favourable pharmacokinetics properties in vivo. They
can circulate in the blood stream for about 12 hours and have much lower concentration of the model payload
(doxorubicin) in the two principal organs/tissues of dose-limiting toxicity of doxorubicin, namely the heart and
the skin. Furthermore, we have demonstrated that the nanoliposomes have minimal toxicity and no
immunogenicity in laboratory animals in the preclinical safety and toxicity studies. The nanoliposomes have
much improved efficacy in inhibiting the growth of human xenograft glioma in immunocompromised mice.
Finally, our nanoliposome can effectively penetrate the blood brain barrier in normal rodents with intact blood
brain barrier, achieving a 50-fold higher delivery of chemotherapy drugs to the brain than some of the currently
available liposomal drugs. Further work in grafting cancer stem cell-targeting RNA aptamers on the surface of
the nanoliposomes shall pave the way for effective chemotherapy against a range of solid tumour with high
efficacy and low side effects.
Expected future outcomes:
The combination of this novel nanoliposome with novel targeting agents (RNA aptamers) shall lead to
effective cancer stem cell-targeted therapy towards the eventual goal of eradicating cancer.
Name of contact:
Professor Wei Duan
Email/Phone no. of contact:
wduan@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 479536
Start Year: 2008
CIA Name: A/Pr Aaron Russell
End Year: 2012
Admin Inst: Deakin University
Grant Type: Career Development Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $380,559
Title of research award:
Molecular targets involved in human muscle atrophy and hypertrophyMolecular targets involved in human
muscle atrophy and hypertrophy
Lay Description (from application):
Muscle wasting is a consequence of aging, cancer, HIV/AIDS, obesity and work/sport injuries. It increases the
risk of injury, impacts on recovery and places an economic burden on our healthcare system. Atrogin-1 and
STARS are muscle specific genes believed to regulate muscle mass. This project aims to determine how human
atrogin-1 and STARS are regulated and how they can influence muscle loss. These studies may provide new
targets for reducing human muscle wasting.
Research achievements (from final report):
It was observed that the expression of the atrogin-1 gene is lower in atrophied muscle of paraplegic patients
and the elderly, while it is increased following acute exercise. These observations are contrary to the suggested
role that atrogin-1 plays a negative role in skeletal muscle by causing muscle atrophy and cautions against
developing therapies to inhibit its activation. It was also observed that the STARS protein increases in response
to muscle contraction in humans. The increase in STARS is a consequence, not a cause, of muscle hypertrophy.
While the STARS protein does not protect against muscle atrophy it is required to maintain muscle cell health
via its regulation of muscle cell proliferation and differentiation. It was identified that STARS gene expression
is controlled by PGC-1α/ERRα, signaling. Importantly, the STARS protein is required to allow PGC-1α to
regulate genes involved in muscle cell metabolism. It was observed that STARS translocates to the nucleus
suggesting that it might bind DNA and directly control gene transcription. As STARS may control gene
transcription and the downstream effects of PGC-1α the relationship between STARS, PGC-1α and
microRNAs that control muscle growth and metabolism was investigated. A suite of microRNAs that are
dysregulated in ALS patients as well as a pertubation in PGC-1α and its downstream targets involved in muscle
growth and metabolism was identified. These achievements support the idea that STARS be considered as a
therapeutic target to improve muscle health.
Expected future outcomes:
Establish the potential of the STARS protein as a therapeutic target to improve muscle function in the elderly
and muscular dystrophies.
Name of contact:
Aaron Russell
Email/Phone no. of contact:
aaron.russell@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 594767
CIA Name: Prof Kylie Ball
Admin Inst: Deakin University
Main RFCD: Public Nutrition Intervention
Total funding: $489,989
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Effectiveness of a skill-building and price reduction intervention for promoting healthy eatingEffectiveness of
a skill-building and price reduction intervention for promoting healthy eating
Lay Description (from application):
Many Australians consume diets that place them at risk of obesity and ill health. Research is required to
identify effective ways of helping people improve their diets. This study will investigate two approaches to
doing so: firstly, by providing people with increased skills in budgeting, selecting and preparing healthy foods;
and secondly, by reducing the prices of healthier foods.
Research achievements (from final report):
The SHELf randomised controlled trial achieved outstanding recruitment and retention success. More than 640
women were recruited within four weeks, with a waiting list accrued. By program completion, 9 months later,
95% of women remained engaged and completed final evaluation surveys. The program showed positive
outcomes on behaviours. The skills-based intervention strategies led to increased fruit consumption; the price
reductions increased fruit and vegetable purchasing; and participants receiving both strategies showed increases
in fruit purchasing and water consumption. Participants rated both approaches as appealing and helpful; many
reported ongoing use of program materials, and commented on the benefits for family members. The program
was recognized through being awarded the 2013 Victorian Health Promotion Foundation Award for Healthy
Eating, presented by the Victorian Premier the Hon. Dr Denis Napthine. The study also led to discussions and
the lead investigator's invited involvement in a Victorian Department of Health working group, focused on
improving the healthfulness of supermarket environments.
Expected future outcomes:
Wide dissemination of main outcomes is planned upon publication. Study materials have been sought by a
variety of community partners, including community health services. Future collaborative projects with study
partners Coles and the National Heart Foundation of Australia are being planned to build upon these successful
results.
Name of contact:
Prof Kylie Ball
Email/Phone no. of contact:
kylie.ball@deakin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 229601
CIA Name: A/Pr Leanne Monterosso
Admin Inst: Edith Cowan University
Main RFCD: Family Care
Total funding: $68,250
Start Year: 2003
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
A National Analysis of the Palliative and Supportive Care Needs of Families whose Children Die from
CancerA National Analysis of the Palliative and Supportive Care Needs of Families whose Children Die from
Cancer
Lay Description (from application):
Palliative and supportive care services for children dying from cancer are underdeveloped in the paediatric
setting. There is an increasing awareness of the need for comprehensive care for these dying children and their
families, however, there is a striking lack of evidence based literature on which to base paediatric palliaitive
and supportive care models of care. This study is the first of its kind in the area of paediatric supportive and
palliative care in Australia. This study will involve five Australian states (WA, SA, VIC, NSW and QLD). To
answer these research questions, a retrospective study will be undertaken because of: a)the profound impact
that caring for a dying child has on the family, b) the potential effects on parents of participating in research
related to the care of their dying child, and c) it has been shown that research undertaken after-death is an
important method for evaluation of the quality of palliative care. The study will provide broad and detailed
description of the palliative and supportive care needs of families whose died from cancer, as well as the types
of care that may be required. The study will therefore, address four research questions: 1. What are the
supportive and palliative care needs of families of children who have died from cancer? 2. To what extent have
the supportive care and palliative care needs of families been met in both the hospital and community settings?
3. How were the supportive and palliative care needs of families of children who died from cancer met? What
were the perceived barriers and facilitating factors associated with the supportive care and palliative care
received by families whose children died from cancer? This study is the first phase of a four-phase research
program that will culminate in the development and testing of models for the provision of palliative and
supportive care for parents of children with life-limiting conditions.
Research achievements (from final report):
Results from this study led to the identification of a number of important features for the delivery of therapeutic
palliative and supportive care for children with cancer and their families. It is crucial that cure-directed and
palliative care are integrated to allow children and their families to benefit from both philosophies of care. The
following key features must be incorporated in the development of palliaitve and supportive care services:, 1.
Provision of education to health professionals and parents regarding the concepts and timing of palliative and
supportive care., 2.
Care that is focused on provision of
home care, with home visits and out-of-hours access to advice from health professionals. , 3. Care that is
individualised and responsive to parents' needs., 4. Care that is coordinated by a full multidisciplinary team of
health professionals., 5. Ready access to in-home respite support.
Expected future outcomes:
1. The education of health professionals involved in the care of children with cancer regarding the concept of
palliative care. , 2. The development of evidence based clinical guidelines for paediatric oncology models of
palliative and supportive based care - in which cure-directed and palliative care are integrated, thus allowing
the child to benefit from both philosophies of care.
Name of contact:
Dr Leanne Monterosso
Email/Phone no. of contact:
l.monterosso@ecu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 534409
CIA Name: Prof Robert Newton
Admin Inst: Edith Cowan University
Main RFCD: Oncology and Carcinogenesis
Total funding: $519,331
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
A Phase III clinical trial of exercise modalities on treatment side-effects in men receiving therapy for prostate
cancerA Phase III clinical trial of exercise modalities on treatment side-effects in men receiving therapy for
prostate cancer
Lay Description (from application):
Hormone therapy is very effective for treating prostate cancer however it produces a number of side effects
including muscle and bone loss, fat gain, and increased risk of death from heart disease and diabetes. In other
populations physical exercise has proven particulary effective for preventing such problems however no long
term studies with prostate cancer patients have ever confirmed this. Knowledge gained from this study has
potential to markedly reduce suffering and increase survival.
Research achievements (from final report):
This randomised controlled trial of different exercise modes is the longest and largest ever completed in men
with prostate cancer to our knowledge. With the primary outcome being bone mineral density it is also one of
the first to address bone loss as a devastating toxicity of androgen deprivation therapy. A particularly unique
feature of this project was the application of "impact" exercise as highly tailored and specific prescription to
slow or possibly prevent bone loss resulting from testosterone suppression. We observed for the first time that
exercise could totally prevent bone loss in men receiving androgen deprivation therapy while men receiving
usual care continued to exhibit declines in bone mineral density. Importantly in terms of current national and
international exercise recommendations a more standard exercise program consisting of aerobic and resistance
training did not appreciably slow bone loss in these patients. This was surprising given previous research
findings in men and women not receiving testosterone suppression received considerable benefit in terms of
bone health from such a standard program. In terms of muscle mass the combination of impact and resistance
training produced significantly greater gains in terms of muscle hypertrophy than the standard program and
usual care resulted in continuing muscle atrophy. This is also a novel finding as it appears that men with
prostate cancer undergoing testosterone deprivation appear much more susceptible to the interference effects of
aerobic exercise undertaken simultaneously with resistance exercise.
Expected future outcomes:
Exercise prescription for cancer patients appears to require much more specific attention to exercise mode and
dosage, in particular if treatment side-effects are to be prioritised for management. The principal future
outcome of this research should be the change to clinical practice with tailored exercise programs rather than
provision of current generic guidelines.
Name of contact:
Professor Rob Newton
Email/Phone no. of contact:
r.newton@ecu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 187644
CIA Name: Prof Graeme Young
Admin Inst: Flinders University
Main RFCD: Preventive Medicine
Total funding: $468,760
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Screening for colorectal cancer: Attitudes affecting participation and implementation of strategies for
improvement.Screening for colorectal cancer: Attitudes affecting participation and implementation of strategies
for improvement.
Lay Description (from application):
There is good evidence that population screening for bowel cancer (CRC), based on the detection of blood in
stools, is effective in reducing deaths from bowel cancer by around 30-40%. Screening depends on the use of a
simple test to identify those who most need the complex and costly test which is capable of accurately
detecting curable cancers and precancer lesions. This can be achieved with moderate effectiveness using simple
tests (FOBTs) which detect microscopic amounts of blood in the faeces. If we are to reduce the rate of death
from CRC, we must have an effective way of encouraging people to do these tests. While much has been
learnt from experience with screening for breast and cervical cancer, CRC presents a series of quite different
issues that have never been comprehensively studied. These are: (1) men and women need to be screened. (2)
symptoms due to CRC are more complex , (3) the high-risk settings for CRC are much more complex), (4) the
community is not as aware of the benefit of screening, (5) the initial test can be performed at personal
convenience in one's home, (6) participants must handle bodily excretions, and (7) inconvenience of attending
a central facility is avoided. We will survey participants and non-participants to more accurately identify the
barriers to screening, and the proportion who have not participated for "informed reasons". To test the real
value of attempts to overcome these, we will then offer screening by various approaches designed to overcome
these. We are in a unique position to do this as we have well-identified populations who have been offered
faecal occult blood test (FOBT)-based screening These studies will assist in the design and implementation of
effective screening programs for the early detection of CRC in Australia, which in the long term will
significantly reduce deaths from this disease.
Research achievements (from final report):
Australia is about to embark in 2006 on a national colorectal cancer screening program. Our findings show how
we can improve participation in screening. People find that the brush-sampling faecal immunochemical tests
(FIT) are preferred over the older technology that required dietary restriction and messy sampling of stools. ,
Behavioural studies have extensively explored the determinants of participation in a setting where we actually
measure the outcome of interventions on participation rather than just examine intentions. In essence,
simplicity and logistic ease of performing testing at home are the keys. Motivators such as perceived benefit,
risk and family history and so on are not as powerful determinants of participation as we might expect.
Including advocacy of screening from a person's own GP achieves a better impact than lay advocacy.
Expected future outcomes:
Better particiaption in screening will eventually lead to a reduction in death rates from colorectal cancer in
Australia and perhaps a reduction in incidence of this cancer.
Name of contact:
Steve Cole
Email/Phone no. of contact:
scoles@rgh.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 275504
CIA Name: Prof David Watson
Admin Inst: Flinders University
Main RFCD: Surgery
Total funding: $510,750
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Barrett's oesophagus and reflux oesophagitis : efficacy of medical vs surgical managementBarrett's oesophagus
and reflux oesophagitis : efficacy of medical vs surgical management
Lay Description (from application):
Gastro-oesophageal reflux disease is very common. In some people it leads to oesophageal cancer, which is
increasing in incidence more rapidly than any other cancer in the developed world. Significant resources are
required for its diagnosis, surveillance and treatment. There are two main forms of treatment, acid suppressing
drugs which may be required for the rest of the person's life, or surgery. The goal of treatment is the control of
the symptoms such as heartburn, and the prevention of cancer. It is relatively easy to determine if the
symptoms are controlled, and both medical and surgical treatments do this. It is not as easy to measure if a
treatment will reduce the risk of cancer, because it takes so long to develop. We will compare a group of
patients with reflux disease treated with drugs with a group treated by surgery. In each group we will take
oesophageal tissue before treatment and compare it with similar tissue taken after treatment. We will look for
reductions in abnormal cells and genes that are in diseased tissue and are important in the development of
cancer. This study will help us understand the mechanisms by which reflux causes damage to the oesophagus
and how it ultimately leads to cancer. We will learn if medical or surgical treatment is better in healing the
underlying damage in the oesophagus, and which treatment is more likely to prevent cancer developing. It may
result in more effective management of reflux in our community and help reduce the number of cases of
oesophageal cancer.
Research achievements (from final report):
This research funded studies which determined how genes function during the development of oesophageal
cancer. We discovered new genes which are involved in the development of cancer, and showed that there are
differences in gene function in patients who have gastreo-oesophageal relfux which is well controlled versus in
those in whom it is porrly controlled. Surgical treatment provided more effective control of reflux compared to
tablets, and this might be important for the subsequent development of cancer in the oesophagus.
Expected future outcomes:
We are extending the findings from this study to look further at the role of reflux in the development of
oesophageal cancer. We are identifying and validating "biomarkers" which might be used to predict the rsik of
cancer development in patients.
Name of contact:
Prof David Watson
Email/Phone no. of contact:
david.watson@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 275544
CIA Name: Prof Peter Mackenzie
Admin Inst: Flinders University
Main RFCD: Gastroenterology and Hepatology
Total funding: $417,750
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Characterization of novel human UDP glycosyltransferasesCharacterization of novel human UDP
glycosyltransferases
Lay Description (from application):
Our defense against the toxic effects of small organic molecules is mediated by families of enzymes found in
the internal membranes of cells, predominantly in the liver and gastrointestinal tract. Many small organic
molecules, such as environmental pollutants, carcinogens and therapeutic drugs, are fat-soluble and will
accumulate in the body to toxic levels unless they are modified by the addition of water-soluble groups. The
modified chemical, in the majority of cases, is less toxic and readily removed from the body. One aim of this
project is to identify and characterize newly discovered enzymes in the family that uses sugar residues to
modify and eliminate fat-soluble chemicals. Their involvement in the detoxification process and how they are
controlled in the cell will be determined. These are the final enzymes in this family remaining to be
characterized in humans. In addition to foreign chemicals and toxins, this enzyme family also regulates the
intracellular concentrations of signalling molecules such as steroid hormones and chemicals that bind to gene
regulatory proteins. Defects and/or variations in these enzymes may alter the levels of these signalling
molecules and lead to uncontrolled cell growth (cancer) or cell death. A second aim of this project is to
determine whether these novel enzymes are involved in controlling signal concentrations and to determine
whether inherited variations in these enzymes will alter the signalling process.
Research achievements (from final report):
Our capacity to eliminate many unwanted fat-soluble chemicals before they accumulate to toxic levels depends
on a family of enzymes that convert them into water-soluble, non toxic products. These chemicals include
environmental toxins, chemicals in our diet and the waste products of metabolic processes. Their products,
being water-soluble, are readily removed in the urine. The enzymes which are involved in their removal, the
UDP glucuronosyltransferases (UGTs) are mainly found in the intestinal tract and the liver. We have
discovered new forms of this enzyme and identified some of the chemicals that they detoxify. One new form,
whose levels differ between individuals, has the capacity to eliminate some chemicals derived from inhaled
smoke and diesel fumes. We have also discovered some of the mechanisms that regulate the expression of this
UGT. This knowledge, combined with knowledge of the chemical selectivities of other UGTs, may help us
predict if an individual is more prone to the adverse effect of a particular fat-soluble chemical or group of
chemicals, because of a reduced capacity to detoxify these chemicals.
Expected future outcomes:
We have identified enzymes involved in the detoxification of many fat-soluble chemicals. Eventually we hope
to understand why the levels of these detoxifying enzymes vary between individuals so that we can devise tests
to predict this variability and hence to predict an individuals response to these chemicals.
Name of contact:
Prof Peter I. Mackenzie
Email/Phone no. of contact:
peter.mackenzie@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 324717
CIA Name: Prof Graeme Young
Admin Inst: Flinders University
Main RFCD: Preventive Medicine
Total funding: $532,425
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
A population based communication strategy to optimise colorectal cancer screening behaviour in Australia.A
population based communication strategy to optimise colorectal cancer screening behaviour in Australia.
Lay Description (from application):
There is good evidence that population screening, based on the detection of blood in faeces, is effective in
reducing deaths from bowel cancer (CRC) by around 30-40%. The process depends on the use of a simple
faecal occult blood test (FOBT) to identify those who need a more complex and costly test (colonoscopy),
which is capable of accurately detecting curable cancers and precancers so that they can be removed. If we are
to reduce deaths from CRC at the population level, we must have an effective way of encouraging as many
people as possible to do FOBT tests. While much has been learnt about how to offer screening from experience
with programs for breast and cervical cancer, CRC screening involves different behavioural, psychological and
social issues. We need to better understand how these factors influence participation in CRC screening. We
plan a series of studies that will lead to improvements in participation in CRC screening programs: a) a survey
of a randomly selected group of the general population to measure a range of behavioural features that are of
importance to CRC screening, especially as they relate to participation. b) an offer of FOBTscreening to those
invited to complete the survey, to match population characteristics with intentions and actual participation, c)
on the basis of these studies, to design new screening program strategies, especially in relation to the
communication of messages to encourage community participation, d) to test the effectiveness of the new
communication strategies by offering FOBT screening to another randomly selected group from the general
population. This will allow us to optimise the delivery of messages that encourage participation. If we can
design a better communication strategy that achieves an increase in screening participation and has minimum
cost implications, we will substantially reduce the number of deaths from CRC in Australia.
Research achievements (from final report):
In this study we have investigated various aspects related to participation in organised screening for bowel
cancer. We have characterised the readiness of the Australian population to undertake bowel cancer screening
and have shown that 35% of people in the population at risk of developing bowel cancer are unaware of the
health issue. The studies provide a baseline for which to compare future surveys of readiness to screen, We
have identified psychosocial and demographic factors that predict both an intention-to-screen and as well as
actual participation in screening ,and have shown that some factors are common in predicting these behaviours.
We have tested in controlled trials the effectiveness of several communication-based strategies to improve
participation in bowel cancer screening. One simple strategy, the use of an advance notification letter to inform
people that they will soon receive an invitation to screen for bowel cancer significantly increased participation
in screening compared to an invitation only. This strategy has now been adopted by National Bowel Cancer
Screening Program., The studies will aid in improving participation rates for mass screening for bowel cancer.
Greater levels of population screening will likely result in reduced numbers of deaths from bowel cancer
through early detection of curable cancers. As pre-cancers or adenomas are also detected, the incidence of
bowel cancer will also be decreased
Expected future outcomes:
The studies will aid in improving participation rates for mass screening for bowel cancer. Greater levels of
population screening will likely result in reduced numbers of deaths from bowel cancer through early detection
of curable cancers. As pre-cancers or adenomas are also detected, the incidence of bowel cancer will also be
decreased.
Name of contact:
Professor Graeme Young
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
graeme.young@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 324719
CIA Name: Prof Graeme Young
Admin Inst: Flinders University
Main RFCD: Gastroenterology
Total funding: $423,750
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of mutational load by chemopreventive agents and implications for molecular pathogenesis of
colorectal cancerRegulation of mutational load by chemopreventive agents and implications for molecular
pathogenesis of colorectal cancer
Lay Description (from application):
In Australia colorectal cancer is the second most common cause of cancer death, however the morbidity and
mortality of colorectal cancer is currently not under control. Identification of safe and practical preventive
agents should aid control. There is increasing evidence that colorectal cancer is associated with endogenous
(internall) and exogenous (external) factors. They cause damage to DNA which might lead to tumour
development if the damage is not repaired. This study will first identify the ability of preventive agents
(aspirin-like drugs, fish oil, and antioxidants) to regulate DNA damage, then examine the effect of combination
of the agents. It will finally determine the ability of agents, or combination of agents, to prevent development
of colorectal cancer using two animal models. Prevention of human CRC by such a strategy should be
feasible. First, evidence indicates that DNA damage is important in tumour initiation. Second, exogenous
regulation of DNA damage, repair and removal seems possible. Epidemiological studies have suggested that
that 30-70% of cancer can potentially be prevented with proper adjustment of diets (fat, fibre, resistant starch)
and supplements of drugs (NSAIDs) or antioxidants (Vitamin, Selenium). Third, preventive strategies are
likely to be feasible. At the population level, they would need to be safe and manageable in the context of
dietary lifestyle, but this can be achieved through a range of food technology developments. In individuals at
high risk, personalised preventive strategies become feasible through doctor-patient contact. This study focuses
on regulation of DNA damage, and its repair and removal during the early stage of tumour development. The
study will provide information if preventive agents, alone or in combination, provide a promising strategy for
colorectal cancer through reduction of genetic damage. They might also identify new biomarkers that facilitate
testing in humans.
Research achievements (from final report):
Dietary habit/factors are important environmental factors influencing colorectal cancer (CRC) risk, one
promising and cost-effective approach to control CRC is to utilise a preventive approach based on dietary
intervention (i.e. use of specific bioactive foods or chemopreventive agents). We have conducted extensive
animal studies, and observed a temporal relationship between formation of DNA damage (O6MeG adducts)
and occurrence of the innate cellular response to this damage (acute apoptotic response) to the cancer-forming
agent AOM. This suggests that this type of damage directly triggeres the cellular response and may be a
primary control mechanism for reducing the cancer-risk associated with such DNA damage. We found dietary
intake of 15% free fish oil as well as 7% microencapsulated fish oil (a formulation designed to ensure delivery
of oil to the large bowel) significantly reduced O6MeG adduct in colonic crypts. We also evaluated a unique,
Australian-developed, selenium-enriched milk protein, and found it strongly protects against CRC through
activiation of the cellular resposne to DNA damage and reduction of resultant gene mutations. This
demonstrates environmental factors, in particular, dietary agents, can play important roles in primary
prevention of CRC through regulation of DNA damage, and maintenance of instability of genes (DNA) in the
colon. By doing this we will be able to focus on the most critical parameters for monitoring dietary intervention
studies in human volunteers. Clearly, a complete understanding of the mechanisms controlling genetic and
epigenetic changes in normal human colonic mucosa and especially how innate cellular responses to DNA
lesions (environmental carcinogens) can be modulated to reduce the consequences of such lesions will provide
for better approaches to cancer prevention.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
The risk of developing cancer is dependent on the amount of DNA damage and/or the capacity to repair this;
both are influenced by environmental (dietary) factors. Our future study seeks to extend our previous work to
determine if dietary agents can enhance DNA repair. This will help us to develop betetr strategies for
prevention of bowel cancer.
Name of contact:
Graeme Young
Email/Phone no. of contact:
graeme.young@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 324728
Start Year: 2005
CIA Name: Prof Peter Mackenzie
End Year: 2009
Admin Inst: Flinders University
Grant Type: Established Career Fellowships
Main RFCD: Pharmacology not elsewhere classified
Total funding: $736,500
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Regulation of the expression of genes in a cell is often dependent on chemicals that are taken up from the
circulation or absorbed through the skin and/or intestine. These can be drugs, metabolites or environmental or
dietary constituents, which bind to receptors to regulate gene expression. I have identified several enzymes
with the capacity to inactivate these chemicals and hence diminish gene expression. As proof-of-principle, we
provide evidence that one of these enzymes has the potential to inhibit the effects of a phytoestrogen in breast
cancer cells. This work may lead to strategies to modulate chemically-controlled signalling pathways for
therapuetic effect. In addition, I have studied two other enzymes that have an important role in controlling the
levels of drugs and fat-soluble environmental chemicals containing nitrogen groups. I have discovered
significant mechanisms that regulate the genes for these enzymes. This knowledge may aid in controlling the
enzymes action, to maximize the therapeutic effects of medicinal drugs and the removal of unwanted chemicals
from the body.
Expected future outcomes:
This work may provide a new approach to control the aberrant expression of genes which is a hallmark of some
diseases and also provide a framework for attempts to manipulate drug and chemical detoxifying enzymes for
therapeutic effect.
Name of contact:
Peter Mackenzie
Email/Phone no. of contact:
Peter.Mackenzie@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 480401
CIA Name: Prof David Watson
Admin Inst: Flinders University
Main RFCD: Surgery
Total funding: $796,144
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Improving the surgical outcomes for Barretts-derived oesophageal adenocarcinoma through early
detection.Improving the surgical outcomes for Barretts-derived oesophageal adenocarcinoma through early
detection.
Lay Description (from application):
Some people with severe reflux develop Barrett's oesophagus, which puts them at high risk of developing
cancer. Patients with Barrett's can be monitored by regular endoscopy to detect cancer early enough so that
they can be treated successfully with surgery. The aim of this work is to identify patients who are at highest
risk of cancer using molecular biomarkers. We will then determine the cost effectiveness of using biomarkers
for surveillance of patients with Barrett's oesophagus.
Research achievements (from final report):
We undertook laboratory studies which defined molecular biomarkers associated with progression from normal
oesophagus to adenocarcinoma via Barrett's oesophagus, and health economic modelling of endoscopic
surveillance for Barrett's oesophagus. The health economic model was developed - initially a treatment model
for disease stages which was analysed to determine the cost-effectiveness treating early stage cancer. This data
was then used to develop a Barrett's oesophagus surveillance model. , Laboratory studies of miRNA and
mRNA biomarkers of reflux, Barrett's oesophagus and oesophageal adenocarcinoma were progressed. We
demonstrated elevated expression of miR-205, miR-143 and miR-145 in squamous epithelium from patients
with reflux, and roles for these miRNAs in regulating epithelial restoration after reflux damage. In-situ
hybridisation localised these miRNAs to the basal layer of the epithelium, and in-vitro studies showed that they
modulate cell growth and death. We progressed studies on the roles of miR-143, miR-145 and miR-215 as
tumour suppressors in Barrett's oesophagus. We have shown that restoration of expression of these miRNAs,
by transfection of cancer cells results in reduced proliferation and increased apoptosis. We also used Western
analysis to demonstrate decreased expression of known growth regulating targets of miR-143, 145 and 215
(DNMT3a, K-Ras, RTKN, DTL) in transfected cells. These studies identified BMP-7 as a novel target of miR215. We have used microarray and PCR validation to demonstrate that the anti-inflammatory and tumour
suppressor miRNAs; let-7a, let-7f, miR-26a and miR-98, are differentially expressed in Barrett's oesophagus
from surgically vs medically treated gastro-oesophageal reflux.
Expected future outcomes:
The data from these this research is underpinning further research evaluating biomarkers which can be used to
predict treatment responses in oesophageal cancer, and these might lead to tailored therapies for oesophageal
cancer.
Name of contact:
Professor David Watson
Email/Phone no. of contact:
david.watson@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 480428
CIA Name: Prof Graeme Young
Admin Inst: Flinders University
Main RFCD: Preventive Medicine
Total funding: $687,439
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Re-participation in screening for colorectal cancer: Behavioural outcomes and predictors.Re-participation in
screening for colorectal cancer: Behavioural outcomes and predictors.
Lay Description (from application):
Screening for bowel cancer (CRC) is an important public health initiative. It is most effective when undertaken
regularly but there is little research on what personal factors relate to ongoing participation in a screening
program. This study will determine the factors associated with ongoing participation in CRC screening and will
lead to better screening programs and improved health benefits. This study directly addresses the Cancer
Australia priority area re improving screening programs.
Research achievements (from final report):
A large population sample was surveyed and categorised according to past bowel cancer screening behaviour
and future intentions.Compared to people who reported that they would maintain regular screening, intending
dropouts reported less social influences to screen, less satisfaction with prior screening, less confidence that
they could complete the screening process and less perceived benefit from screening, were more likely to be
unaware of the need for repeat screening and were more likely to not have private health insurance. Intermittent
screeners were less likely to have planned when they will next screen and reported greater barriers to rescreening. , Survey respondents were invited to participate in three rounds of a research scale bowel cancer
screening program. The participation rate at each round was 58.5%, 66.6% and 73% respectively. Over three
rounds, 43% of people consistently returned tests offered through the study. When screening outside the study
was included, the participation rate was 60.3%. Thus study participation rates significantly underestimated the
true population screening rate., Associations between ongoing participation and participants' demographic and
psychosocial variables were identified. Ongoing participants were significantly more likely to be older, married
and no longer working full time. Gender, country of birth or language spoken at home were not associated with
poorer rates of rescreening. Psychosocial characteristics had little influence on re-participation in screening.
Dissatisfaction with previous screening adversley affected participation in later rounds. , These results provide
a useful foundation for further research into the development and trail of interventions to encourage reparticipation in bowel cancer screening.
Expected future outcomes:
Further analyses will explore the impact of additional variables from data obtained from an end of study
survey. The identification of population groups that have poor re-screening rates potentially allows the
development of strategies to improve ongoing screening that directly target those groups.
Name of contact:
Prof Graeme Young
Email/Phone no. of contact:
graeme.young@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 480471
Start Year: 2008
CIA Name: Dr Christine Sanderson
End Year: 2010
Admin Inst: Flinders University
Grant Type: SRDC - Research
Main RFCD: Clinical Pharmacology and Therapeutics
Total funding: $50,000
Title of research award:
Adouble-blind placebo contorolled study of subcutaneous ketamine in the management of cancer painAdoubleblind placebo contorolled study of subcutaneous ketamine in the management of cancer pain
Lay Description (from application):
Palliative care teams are studying an anaesthetic, ketamine, used at low doses for cancer pain which is not
responsive to opioid drugs. Clinical experience suggests ketamine may help in neuropathic pain, which is due
to nerve damage and is common in cancer. The study involves five days of treatment at three doses of
ketamine, to see how well pain is controlled on each dose. The highest dose given will be that which gives
good pain control. The study compares ketamine with a placebo, and patients keep on their usual pain
medicines. Participants are randomised to have ketamine or the placebo. The study looks at pain control,
quality of life, ketamine side effects, and change in need for usual pain medicines. This is the first national
clinical study of a new palliative care research network, the Palliative Care Clinical Trials Collaborative
(PaCCSC). It is hoped that if ketamine is proven safe and effective in difficult cancer pain, it will be more
easily available for cancer patients.
Research achievements (from final report):
This randomised controlled trial of ketamine for treating cancer pain in a palliative care population has
provided the strongest evidence yet to guide treatment decisions, showing that ketamine is no more effective
than placebo in the management of cancer pain, and furthermore, that it is associated with significant toxicity.
The use of ketamine has previously been common in palliative care, based on uncontrolled studies, but no
adequately powered study with a placebo arm had previously been completed to answer the questions about its
effectiveness. The completed study provides a decisive contribution to palliative care practice, and will lead to
a review of pain management protocols based on this evidence.
Expected future outcomes:
The dissemination strategy for the results of this trial will ensure that its findings are widely discussed, both in
Autralia and internationally. The goal of this strategy is for palliative care practitioners and organisations to
review and limit their use of ketamine based on the compelling evidence from this study of its lack of clinical
benefit.
Name of contact:
Professor David Currow
Email/Phone no. of contact:
David.Currow@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 480476
CIA Name: A/Pr Meera Agar
Admin Inst: Flinders University
Main RFCD: Oncology and Carcinogenesis
Total funding: $50,000
Start Year: 2008
End Year: 2011
Grant Type: SRDC - Research
Title of research award:
RCT of risperidone versus haloperidol versus placebo with rescue haloperidol in delirium in palliative careRCT
of risperidone versus haloperidol versus placebo with rescue haloperidol in delirium in palliative care
Lay Description (from application):
A simple definition of delirium is an acute confusional state that occurs when someone is unwell. It can
manifest with many symptoms of varying severity, including confusion, restlessness, poor concentration and
disturbance of sleep pattern. Delirium is a common problem when someone is unwell. Experience suggests that
medications such as haloperidol and risperidone may be useful in managing these symptoms, however these
have not been studied in detail in palliative care. This study is comparing the three approaches: use of
risperidone given regularly, use of haloperidol given regularly, and use of haloperidol given as needed for
symptoms of agitation, hallucinations and restlessness related to delirium in patients being cared for in
palliative care settings. This study will compare how well these medications control delirium symptoms (from
health professional, patient and caregiver perspectives) and also monitor their side effects over a five-day
period, and follow longer term outcomes for 6 months (function and location of care).
Research achievements (from final report):
, This research development grant supported the recruitment of 31 participants to this randomised controlled
trial. , Recruitment of 31 participants to a randomised study of delirium within 12 months. Internationally
delirium studies have been identified as significantly challenging due to unstable nature of the clinical
population and person responsible consent issues; so this recruitment rate is excellent for a RCT in delirium.
This study will benefit patients who experience delirium in palliative care, but also in any health care setting
due to the paucity of RCT evidence. It specifically will provide a caregiver perspective on treatment efficacy in
reducing distress. It will also benefit health care service planning due to inclusion of economic evaluation of
the impact of delirium and its treatment. The biomarker substudy may provide insight into directions for new
therapeutics which may benefit patients with delirium.
Expected future outcomes:
Completion of the RCT with 165 participants and the comparative outcomes of haloperidol and risiperidone
versus placebo (with best nonpharmacological care) will be available.
Name of contact:
A/Prof Meera Agar
Email/Phone no. of contact:
meera.agar@sswahs.nsw.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 535079
CIA Name: Dr Richard Le Leu
Admin Inst: Flinders University
Main RFCD: Gastroenterology and Hepatology
Total funding: $604,797
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Dietary protein-induced DNA damage in colon and consequences for colorectal oncogenesisDietary proteininduced DNA damage in colon and consequences for colorectal oncogenesis
Lay Description (from application):
This research will explore the effects of dietary protein on genetic damage to cells lining the large bowel and
risk of developing colorectal cancer. We will determine the degree and type of DNA damage resulting from
increased protein, the cellular response to this DNA damage, whether it increases risk for developing bowel
cancer and whether it can be minimised by other foods in both an animal model and humans.
Research achievements (from final report):
We are the first research group to show that consumption of a high red meat diet can increase pro-mutagenic
DNA adducts (base changes in DNA) in the colon of mice. Furthermore we demonstrated that delivery of a
fermentable carbohydrate to the colon (as resistant starch) can reduce the adduct formation induced from the
high red meat diet. We have also shown for the first time in humans that feeding a diet containing 300g of red
meat per day over a 4-week period to healthy participants can increase pro-mutagenic adduct formation in their
rectal crypts. Feeding a diet high in resistant starch prior to this high red meat diet can protect the participants
against this increase in the promutagenic adduct.In a randomised cross-over study, we also found that a high
red meat diet increased levels of specific oncogenic mature microRNAs (which are small non-coding RNA
molecules which can regulate gene expression) in the rectal mucosa of healthy human volunteers, and
corresponded with increased cell proliferation. Conversely, resistant starch supplementation restored these
microRNAs to baseline levels . The differential regulation of the oncogenic microRNAs cluster by these
dietary factors may explain, at least in part, the respective risk profiles of high red meat and resistant starch.
Our findings support increased resistant starch consumption as a means of reducing risk associated with a high
red meat diet.
Expected future outcomes:
Further raise concern of the adverse effects of consuming a high red meat diet, including the importance of
balancing red meat intake with foods rich in resistant starch. This work is likely to lead to further research into
the protective effects of consuming a diet high in resistant starch.
Name of contact:
Dr Richard Le Leu
Email/Phone no. of contact:
richard.leleu@csiro.au
NHMRC Research Achievements - SUMMARY
Grant ID: 595964
CIA Name: Prof David Watson
Admin Inst: Flinders University
Main RFCD: Cancer Diagnosis
Total funding: $659,990
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
MICRORNA PREDICTORS OF OESOPHAGEAL TUMOUR RESPONSE TO CHEMOTHERAPY AND
RADIOTHERAPYMICRORNA PREDICTORS OF OESOPHAGEAL TUMOUR RESPONSE TO
CHEMOTHERAPY AND RADIOTHERAPY
Lay Description (from application):
Chemoradiotherapy (CRT) is used for the treatment of oesophageal cancer before surgical resection, and for
patients not undergoing surgery. However, it is unsuccessful for many, causing side effects, no clinical gain,
and delaying surgery. MicroRNAs are small molecules that control cellular functions. This project will identify
miRNA markers which are able to predict cancer response to CRT, and this will help clinical decision making
for individualized treatment.
Research achievements (from final report):
Genes in cancer cells control the way the cancer cells grow and behave. Whether a cancer will be killed by
treatment such as chemotherapy and radiotherapy, or whether a cancer is resistant to these agents, can depend
on whether a gene (or genes) are switched on or off in the cancer cells before treatment begins. Whether a gene
(or genes) are switched on or off is termed the 'gene expression profile', and we are able to measure gene
expression profiles in the lab. Our overall aim was to find pre-treatment gene expression profiles in
oesophageal cancer tissue which corresponded to they way in which the tumour responded to
chemoradiotherapy treatment. We included tissue samples that were collected during the course of the study, as
well as tissue samples that were collected over ten years ago, and confirmed that we could measure gene
expression in all of these samples even the old samples. We classified the cancer tissue samples according to
the response to chemoradiotherapy, as determined from clinical case notes and expert review. We compared
the gene expression signatures in the response and non-response groups to identify the genes that are switched
off in one group and on in the other group. We found over 20 genes which could be used to predict the way a
tumour will respond to chemotherapy. This information has the potential to benefit future clinical decision
making in order to optimise the treatment pathway for oesophageal cancer patients.
Expected future outcomes:
We anticipate that the gene expression profiles identified in our study will undergo further testing to further
determine their potential clinical utility for predicting whether a patient's oesophageal cancer will respond to
chemoradiotherapy
Name of contact:
David Watson
Email/Phone no. of contact:
david.watson@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1006242
CIA Name: Prof Graeme Young
Admin Inst: Flinders University
Main RFCD: Preventive Medicine
Total funding: $767,383
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Evaluation of blood-based screening tests for colorectal neoplasia; from biomarker candidates to accurate and
acceptable testsEvaluation of blood-based screening tests for colorectal neoplasia; from biomarker candidates
to accurate and acceptable tests
Lay Description (from application):
Current bowel cancer screening tests require people to collect a stool sample. While able to be done at home,
this creates certain inconveniences and has other barriers to its use including being distasteful to some. Also,
even though stool tests are useful they are not as accurate as we would like. We have discovered a molecule in
the blood of patients with bowel cancer that could, if configured as a screening test, serve to be of even greater
accuracy and also be more acceptable to people.
Research achievements (from final report):
We have refined and validated a test for methylated DNA in plasma that could be applied as a screening test for
colorectal cancer (CRC). Specifically, we have chosen the final panel of markers and their nature. A
multiplexed assay was then developed for use in plasma. We then validated the chosen panel (2-gene
methylated IKZF1 and BCAT1) across the full spectrum of neoplastic and benign lesions encountered in the
colon, in cases of proven clinical status (by colonoscopy) and in those also doing a faecal immunochemical
screening test (FIT). Against colonoscopy, overall sensitivity for cancer is 70% - greater than that shown for
the RCT-proven guaiac-FOBT (gFOBT) which is insensitive for adenomas but known to reduce CRC mortality
when used for screening. However, at this stage the 2-gene panel is no more sensitive for adenomas than is
gFOBT. Thus we predict the 2-gene panel will not replace FIT as the primary screening test but may well
provide a means of "rescuing" people for screening who will not do a FIT. Data comparing the 2-gene test to
FIT are still being acquired (due June 30). Concerning specificity, the 2-gene test is superior to FIT and is not
affected by overt bleeding or benign colonic disorders so it may also be useful for people who cannot use a
faecal ocult blood test for CRC screening. As the markers disappear from blood after cancer resection, the test
could be useful to monitor CRC recurrence in people who have had therapy for CRC.
Expected future outcomes:
Use of the new test alone or in combination with existing screening tests will result in a greater proportion of
the target population participating in screeningfor CRC. It will also provide a screening option for those where
FOBT is contrindicated and a new marker for monitoring CRC recurrence.
Name of contact:
Prof Graeme Young
Email/Phone no. of contact:
graeme.young@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1007501
CIA Name: Dr Ying Hu
Admin Inst: Flinders University
Main RFCD: Cancer Cell Biology
Total funding: $632,924
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Defining biomarkers of colorectal cancer prevention by dietary agents and translation to human intervention
studiesDefining biomarkers of colorectal cancer prevention by dietary agents and translation to human
intervention studies
Lay Description (from application):
This research will explore dietary agents for their ability to regulate the damage to DNA that is responsible for
causing bowel cancer. The plan is to identify a dietary approach that will effectively reduce the risk of colon
cancer. The science will be tested in animal models followed by initial human experiments aimed at testing the
relevance to humans.
Research achievements (from final report):
Environmental carcinogens can induce DNA lesions in large bowel. If the lesions are not repaired by DNA
repair enzyme (i.e. MGMT) or removed by the process of programmed cell death (apoptosis), these leasions
have the potential to develop to bowel cancer. We found that both MGMT and apoptosis are important defence
mechanisms to reduce DNA damage and maintain a healthy genome. Moreover, we found that the mineral
selenium (Se) and great tea can manipulate MGMT and apoptosis in a positive manner to stabilise genes. We
have further examined if a combination of Se and green tea provides protection against bowel cancer. Using a
rat bowel cancer model, we demonstrated for the first time that this combination is significantly more effective
in suppressing bowel cancer development than either Se or green tea alone. The underlying mechanisms of the
enhanced protection by the combination are associated with regulation of cancer-generating changes and so
reduce the risk of bowel cancer. , A specific form of dietary fibre known as resistant starch (RS) has aniinflammation and anti-cancer effects, so far there have been no animal studies where prevention or treatment of
inflammation-associated bowel cancer using RS has been evaluated. We have established animal models of
inflammation and bowel cancer, we found for the first time that RS can act in a beneficial manner to protect
against bowel cancer by producing bioactive compounds in the large bowel, healing inflammation and
restoring a healthy gut bacteria. Thus, RS may be beneficial for bowel cancer prevention and/or treatment in
individuals affected by inflammatory bowel diseases.
Expected future outcomes:
This work is likely to lead to translational research into the protective effects of combining dietary agents with
different mechanisms of actions for bowel cancer prevention. This work also suggests RS may be beneficial for
IBD patients and may have chemopreventive and chemotherapeutic potential for patients with colitisassociated bowel cancer.
Name of contact:
Dr Ying Hu
Email/Phone no. of contact:
ying.hu@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 188821
Start Year: 2002
CIA Name: Prof Rob Sutherland
End Year: 2006
Admin Inst: Garvan Institute of Medical Research Grant Type: Established Career Fellowships
Main RFCD: Oncology and Carcinogenesis
Total funding: $765,000
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
The aims of this research were to further define molecular mechanisms of cancer causation and progression and
to employ this knowledge to develop new markers of cancer diagnosis and disease progression and define new
molecular targets for future development of new cancer drugs. Major achievements included:, - identifying new
molecular mechanisms through which the female hormone oestrogen drives cell proliferation in breast cancer, employing this knowledge to define novel mechanisms of tamoxifen resistance in breast cancer, especially the
role of the oncoproteins c-Myc, cyclin D1 and cyclin E, - using genome-wide approaches to identify molecular
markers of disease outcome in prostate cancer, - validating one such marker, AZGP-1, as the first molecular
marker of metastatic prostate cancer, - applying similar approaches to ovarian and pancreatic cancer to identify
new markers of disease phenotype and outcome.
Expected future outcomes:
These discoveries form the basis for the development of new molecular markers of disease that can be rapidly
translated into the routine clinical management of cancer. To date we have initiated 2 prospective clinical trials
to validate AZGP1 as a marker of prostate cancer metastasis and S100A2 as a marker of therapeutic response
to resection in pancreatic cancer.
Name of contact:
Professor Rob Sutherland
Email/Phone no. of contact:
r.sutherland@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 202907
Start Year: 2002
CIA Name: Prof Susan Clark
End Year: 2004
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Gene Expression
Total funding: $422,310
Title of research award:
Analysis of very early cancer-related methylation abnomalitiesAnalysis of very early cancer-related
methylation abnomalities
Lay Description (from application):
The factors that are involved in triggering cancer are still unknown. Increasing evidence however indicates
that the DNA in the pre-cancer cell becomes modified leading to altered expression of important genes called
tumour suppressor genes. Often the DNA is deleted or mutated but it can also become chemically changed by
a process called DNA methylation. We have found that an important tumour suppressor gene called p16 is
inactivated and chemically methylated in breast epithelial cells at the stage when the cell changes to a precancer cell. This grant is aimed at finding what triggers the silencing and methylation of the p16 gene in this
early pre-cancer stage. We also plan to identify other genes are methylated and undergo inactivation the precancer breast cells. These results will have an impact on understanding the molecular mechanism that makes
a breast cell susceptible to cancer and may lead to insights into new prevention and treatment strategies.
Research achievements (from final report):
The factors that are involved in trigger cancer are unknown. Increasing evidence however indicates that the
DNA in the pre-cancer cell becomes modified leading to altered expression of important genes called tumour
suppressor genes. Often the DNA is deleted or mutated but it can also become chemically changed by a process
called DNA methylation. We have found that an important tumour suppressor gene called p16 is inactivated
and chemically methylated in breast epithelial cells at the stage when the cell changes to a pre-cancer cell. This
grant was successful in providing important evidence to the mechanism that triggers the silencing and
methylation of the p16 gene in this early pre-cancer stage. We have also discovered other tumour related genes
that become methylated and undergo inactivation in the pre-cancer breast cells. These results have an impact
on understanding the molecular mechanism that makes a breast cell susceptible to cancer and has to insights
into new possible markers for early breast cancer diagnosis.
Expected future outcomes:
We showed that tumour suppressor gene silencing precedes DNA and histone methylation and are now
extending this observation to other genes in this cell system. We also discovered other genes that become
methylated in the pre-cancer breast cells and have developed sensitive assays to determine the extent of
methylation in cancer tissue and blood for possible use in early breast cancer diagnosis.
Name of contact:
Susan Clark
Email/Phone no. of contact:
s.clark@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 230814
Start Year: 2003
CIA Name: Prof Roger Daly
End Year: 2003
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Oncology and Carcinogenesis
Total funding: $141,750
Title of research award:
Regulation of mitogenic signalling via the Gab2 docking proteinRegulation of mitogenic signalling via the
Gab2 docking protein
Lay Description (from application):
Cell proliferation is regulated by growth factors which bind to specific receptors on the cell surface. These
receptors then transmit a signal to the interior of the cell instructing it to divide. Inside the cell, the signal is
transmitted by signalling proteins. Importantly, aberrant signalling by growth factor receptors or intracellular
signalling molecules can contribute to cancer. We have recently demonstrated that the signalling protein Gab2
is overexpressed in a subset of breast cancers. Furthermore, we have identified that another protein, termed
PKB, can 'switch off' signalling by Gab2, and that deregulated signalling by Gab2 can make cells cancerous.
The aim of this project is to characterize how PKB regulates Gab2, and to investigate whether this mechanism
is impaired in human cancers, leading to enhanced Gab2 signalling. The research will provide important
information regarding how growth factor signals are transmitted inside cells, and may identify a new cancercausing gene.
Research achievements (from final report):
Gab2 is a protein that functions inside the cell to transmit signals from growth factor receptors on the cell
surface to the nucleus, resulting in cell division. Previously, we had determined that expression of an altered
form of Gab2 in cells made them cancerous. Furthermore, we demonstrated that Gab2 is linked to cancer
development, because it is overexpressed in breast cancer. The aim of the grant was to determine how
proliferative signalling by Gab2 is regulated. In the first year of the grant we determined that Gab2 binds 14-33 proteins at multiple sites, and this is likely to regulate the action of Gab2. Also, the binding of Gab2 to
growth factor receptors via the adapter protein Grb2, as well as its interaction with two downstream effectors,
PI3-kinase and Shp2, are important for the transmission of proliferative signals. Ultimately, this research may
lead to the development of novel therapeutic approaches that block protein-protein interactions mediated by
Gab2 and thereby inhibit cancer cell growth. The project grant ran from January 1st- December 31st 2003
before being relinquished due to the award of a Program Grant.
Expected future outcomes:
Research in this area may lead to the development of novel therapeutic approaches for cancer aimed at
blocking Gab2 or Shp2 function.
Name of contact:
A/Prof Roger Daly
Email/Phone no. of contact:
r.daly@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 230842
Start Year: 2003
CIA Name: Prof David James
End Year: 2005
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $440,250
Title of research award:
Mechanism of action of Sec1p-like proteins in Membrane Trafficking.Mechanism of action of Sec1p-like
proteins in Membrane Trafficking.
Lay Description (from application):
One of the most important evolutionary changes that has occurred is the development of intracellular
compartments. All eukaryotic cells possess numerous membrane-encased structures which provide the basis
for intracellular specialisation. For example, in order to degrade unwanted components cells have developed
degradative enzymes. It is vital for the cell that these enzymes are sequestered away from other cellular
components to avoid destruction of valuable molecules. In addition, the cell has developed a complex
assembly line of modifications that are added to proteins in a specific order as they travel to their final
destination within the cell. This necessitates the accurate passage of molecules between compartments, a
process known as vesicle transport. To orchestrate the complex network of vesicular transport steps between
all of the various intracellular compartments it is necessary to employ complex machinery to guide and check
that these steps occur with high fidelity. The goal of our research proposal is to define the function of one of
the molecules involved in this control process, the so-called Sec1p proteins. The strength of our proposal lies
in the diversity of our approach. We intend to explore the molecular advantages of a relatively simple
eukaryotic organism, a yeast cell, and apply the findings obtained from this cell to a more complex but highly
related vesicular transport process; that of the insulin-regulated movement of a glucose transporter in
mammalian fat and muscle cells. While we intend to apply our findings to the treatment of patients with
diabetes, it is our ultimate goal to be able to learn more about this fundamental cell biological process so that
we can apply our knowledge to understanding many different disease states.
Research achievements (from final report):
The movement of proteins within the cell is fundamental to almost all biological processes. There are now
many diseases that appear to be due to disruptions in the process of protein movement within cells, including
Parkinson's disease, Huntington's disease, as well as various kinds of cancer. Although the function of proteins
within cells is very similar across all organisms, our understanding of the molecular machinery that governs
this function is very rudimentary. In this study, we have begun to unravel the workings of one of the proteins
that is involved in this process, which we believe will provide us with important clues to fundamental questions
about the relationship between protein movement and disease. .
Expected future outcomes:
In the future we hope to be able to define the function of the protein we have identified in much greater detail.
We hope to solve the atomic structure of this molecule, and then to use this information to pinpoint exactly
how it functions in the living cell and how this may relate to different disease states.
Name of contact:
Professor David E James
Email/Phone no. of contact:
d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 230868
Start Year: 2003
CIA Name: A/Pr Andrew Biankin
End Year: 2006
Admin Inst: Garvan Institute of Medical Research Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Oncology and Carcinogenesis
Total funding: $319,903
Title of research award:
Novel Gene Discovery in the Development and Progression of Pancreatic Cancer.Novel Gene Discovery in the
Development and Progression of Pancreatic Cancer.
Lay Description (from application):
Not Available
Research achievements (from final report):
During the fellowship Dr Biankin generated 10 manuscripts that were either publisher or in press in leading
journals during the time of his fellowship/ These included the Journal of Clinical Oncology, Cancer Research
and Development. He was an invited member of NIH sponsored international expert panels for precursor
lesions of pancreatic cancer and mouse models of pancreatic cancer. As recognistion of his contributions
during that period he received the Excellence in Translational Research Award at Johns Hopkins and was
awarded the Cure Cancer Australia Young Researcher of the Year in 2005.
Expected future outcomes:
Dr. Biankin expects to continue making significant contributions to pancreatic cancer research and currently
leads the Pancreatic Cancer Research Group at the Garvan Institute.
Name of contact:
Rob Sutherland
Email/Phone no. of contact:
r.sutherland@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 276408
Start Year: 2003
CIA Name: Prof Rob Sutherland
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: Programs
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $5,043,012
Title of research award:
Control of cell proliferation and differentiation in breast and prostate cancerControl of cell proliferation and
differentiation in breast and prostate cancer
Lay Description (from application):
Breast and prostate cancer are the most commonly diagnosed cancers in women and men
respectively, together accounting for >25% of all newly diagnosed cancers in Australia and other
developed countries. Although significant improvements in the management of these cancers
have occurred in the past 20 years further research is needed to better understand the molecular
mechanisms of disease development and progression. Such research is critical to the better
management and ultimate control of these diseases through better treatments and prevention. A
multidisciplinary team of cancer researchers at the Garvan Institute of Medical Research, with a
10 year track record of discovery and application of their research into breast and prostate cancer,
will employ state-of-the-art research tools to identify new molecules and molecular pathways
involved in these diseases. This new information will facilitate the improved management of
these cancers through improved assessment of disease progression at the time of diagnosis and
the development of new drugs and strategies for treatment and prevention.
Research achievements (from final report):
The overall aim of the research funded by this Program Grant was to characterize molecular mechanisms that
lead to the development and progression of breast and prostate cancer, in order to improve the treatment and
clinical management of these malignancies. This research led to the identification of a 'master regulator' of
normal tissue development in the mammary gland as well as a variety of proteins that control the growth of
breast and prostate cancer cells through their involvement in steroid and growth factor action. Several of these
are directly implicated in cancer development since they exhibit the potential to induce cancer when activated
('oncogenes') or switched off ('tumour suppressors'). In addition, novel mechanisms of drug resistance were
identified, which highlighted certain proteins as potential markers of responsiveness to established therapies.
During the course of the grant, we developed extensive cancer tissue banks and associated clinical databases
and used these to identify novel therapeutic targets in breast and prostate cancer as well as molecular markers
of cancer subtype and disease progression. In particular, this work led to prospective clinical testing of the first
molecular biomarker of metastatic prostate cancer, AZGP-1. Overall this research has provided fundamental
insights into the molecular and cellular biology of breast and prostate cancer and identified potential strategies
for improving the morbidity and mortality of patients afflicted by these diseases, that involve development of
novel targeted therapies or use of molecular markers to stream patients into optimal treatment regimens.
Expected future outcomes:
Expected future outcomes are improved treatment and clinical management of breast and prostate cancer
patients. In particular, we have identified specific biomarkers and gene expression 'signatures' that predict
patient prognosis or response to therapy, and we expect that these will represent important tools for selecting
optimal treatments for patients.
Name of contact:
Professor Robert Sutherland
Email/Phone no. of contact:
r.sutherland@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 276506
Start Year: 2004
CIA Name: Prof Roger Daly
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: Established Career Fellowships
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $638,750
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
During the course of this fellowship, I have continued to make major contributions to our understanding of how
hormones and growth factors stimulate particular responses in their target cells. My research has identified that
two signalling proteins, Grb10 and Grb14, repress insulin responses, and has revealed in molecular detail how
Grb14 exerts its effects on the insulin receptor. In terms of cancer research, it has identified a new role for
cortactin, a protein often expressed at high levels in breast and head neck cancers. This work has determined
that cortactin acts by sustaining signalling by particular growth factor receptors on cancer cells. Finally, my
work has characterized a new mechanism regulating signalling by the oncogene product Gab2, and has
identified new roles for this protein, including promotion of cancer cell spread. Overall, this research may lead
to new therapeutic approaches for treatment of the insulin resistance associated with Type 2 Diabetes, and for
blocking the unrestrained signalling characteristic of cancer cells.
Expected future outcomes:
Expected future outcomes are the development of therapeutic approaches for Type 2 Diabetes and cancer based
on selective inhibition of particular signalling proteins, and the use of such proteins as cancer biomarkers that
aid stratification of patients for optimal therapies.
Name of contact:
Professor Roger Daly
Email/Phone no. of contact:
r.daly@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 293810
Start Year: 2004
CIA Name: Prof Susan Clark
End Year: 2006
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Gene Expression
Total funding: $333,000
Title of research award:
DNA Methylation and Gene Silencing in CancerDNA Methylation and Gene Silencing in Cancer
Lay Description (from application):
Congenital hemiplegia occurs in over 1 million children under 21 years of age in the industrialized world. It is
the most common type of cerebral palsy, accounting for 36 percent of children diagnosed with this lifelong
condition. We intend to determine if a promising new treatment approach is effective in providing a superior
and lasting benefit, compared to conventional techniques. Children with hemiplegia usually have the
intellectual capacity to attend normal school; however the impaired arm reduces independence in activities of
daily living and can compromise their ability to participate in educational, leisure and vocational roles.
Previously we have shown that a program of upper limb rehabilitation in children with spasticity was effective
in improving participation and quality of life. We have also shown that rehabilitation combined with
Botulinum toxin A (Botox) can further improve functional activity. We believe that a new method of therapy,
that has been used effectively in Adults with stroke, called Constraint Induced Movement Therapy (CIMT)
may also be beneficial in the treatment of children with congenital hemiplegia. In CIMT, the unimpaired arm is
constrained in a glove to promote use of the impaired arm (hemiplegic arm). We predict that, combined with
the Botox treatment, CIMT will provide a superior and longer lasting benefit compared to standard
rehabilitation combined with Botox. The primary aim of our study is to test this hypothesis in a controlled trial.
A secondary aim is to further our understanding of the central neurovascular mechanisms underlying changes
in upper limb function. To achieve this, we will use Functional Magnetic Resonance Imaging (fMRI) and
Transcranial Magnetic Stimulation (TMS) to measure central activation in the parts of the brain controlling
movement. Improving our understanding of the mechanisms involved in this condition is an essential next step
towards providing a more effective and long lasting treatment.
Research achievements (from final report):
Aberrant methylation of tumour suppressor genes is a very early step in cancer progression and is commonly
associated with silencing of these genes in cancer. However unlike DNA mutation or gene deletion,
methylation is a reversible modification of the DNA. Therefore reprogramming the methylation state of the
cancer cell has the potential to reactivate critical tumour suppressor genes. In this study we demonstrated that
tumour suppressor gene silencing often preceded DNA methylation in cancer and that aberrant methylation can
occur in a normal cell. Therefore cancer specific factors are not required for aberrant methylation. We
demonstrated that gene suppression co-incided with chromatin remodelling resulting in DNA methyaltion and
further gene inactiavtion. The results from this study have provided invaluable insight as to the mechanism
responsible for the methylation of specific gene sets in different cancer types.
Expected future outcomes:
Our study suggests that genes susceptible to methylation in cancer are those genes previously downregulated in
the progenitor cancer cell. Without protection of active gene transcription, CpG sites within the CpG island
promoter are targets for hypermethylation. This has major ramifications in identification of novel cancer
biomarkers and epigenetic-based therapies.
Name of contact:
Susan Clark
Email/Phone no. of contact:
s.clark@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 302118
Start Year: 2004
CIA Name: Dr Stuart Tangye
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: Career Development Fellowships
Main RFCD: Medical and Health Sciences not elsewhere classified
Total funding: $421,375
Title of research award:
Molecular and cellular regulation of human lymphocyte differentiation in health and diseaseMolecular and
cellular regulation of human lymphocyte differentiation in health and disease
Lay Description (from application):
Not Available
Research achievements (from final report):
There were 2 major focuses of the research performed by myself, and my research team, during the awarding
of the RD Wright Career Development Award. First, to identify defects in the development and function of
immune cells (lymphocytes) in patients with X-linked lymphoproliferative disease (XLP) that underly the
development of this inherited human immunodeficiency in affected individuals. The significant findings from
this line of investigation were the following: (a) a lack of memory B cells due to an inability of CD4+ helper T
cells to provide the appropriate signals which instructs B cells to become memory cells. As a result, XLP
patients have an impaired generation of a memory immune response, which is important for the production and
maintenance of long-lived immunity which protects us from re-infection with the same infectious pathogens
during our lifetime; (b) a block in B-cell development such that there was an increase in the frequency of
immature B cells, which would also contribute to reduced memory responses; (c) an complete inability to
generate a specialised subset of CD4+ T cells termed NKT cells which are invovled in immune responses
against tumours and viruses. These findings explain several features of the clincal presentation of XLP and
revealed strategies by which the immune responses of XLP patients could be improved. Second, to identify
molecules involved in regulating the response of different subsets of human B cells. This resulted in the
identification of genes expressed by naïve B cells that are important in restraining the response of these cells,
as well as of genes expressed by helper T cells that are strong inducers of B-cell differentiation and effector
function
Expected future outcomes:
o Improved diagnosis, prognosis and treatments for patients with not only XLP but other immunodeficiencies
characterised by impaired B-cell maturation and function, o identification of molecules that could be targetted
to modulate the magnitude of an immune response eg increase it in cases of immunodeficiency, and decrease in
cases of autoimmunity/excessive inflammation
Name of contact:
Stuart Tangye
Email/Phone no. of contact:
s.tangye@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325604
Start Year: 2005
CIA Name: Prof David James
End Year: 2007
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $469,500
Title of research award:
Molecular regulation of GLUT4 targeting.Molecular regulation of GLUT4 targeting.
Lay Description (from application):
Insulin resistance (the inability of ordinarily insulin-sensitive tissues such as muscle and adipose tisse to
respond to insulin) contributes to a number of diseases including diabetes and obesity. A key metabolic step in
these tissues is the uptake of glucose from the blood stream. This step is accelerated by insulin thus allowing
efficient clearance of glucose from the bloodstream after a meal. Our laboratory has played a major role in
showing that insulin regulates glucose uptake into muscle and adipose tissue by stimulating the movement of a
glucose transport protein from inside the cell to the cell surface. The purpose of this proposal is to dissect the
molecular mechanisms by which this glucose transporter can be held inside the cell in the absence of insulin
and then allowed to be released from this site moving to the surface in the presence of insulin. Our studies over
the past 5 years have brought us much closer to understanding this process in detail. The identification of the
molecules responsible for this regulatory step will not only aid our understanding of this process but it will also
provide a valuable target for development of therapeutic agents that can be used to combat insulin resistance.
Research achievements (from final report):
1. Tissue specificity. Conditional c-Cbl-/- mice have now gone germ line and mice are planned to be shipped to
the Garvan within the next month. , 2. The role of c-Cbl in the fat cell. We have studied insulin signalling
pathways in adipocytes from c-Cbl-/- mice and have found no significant difference compared to wild type
animals. We are currently developing fat cell transplantation techniques to examine the effects of c-Cbl fat
when transplanted into a wild type recipient. , 3. Energy expenditure. The activity of a series of oxidative
enzymes has been measured and we have found no significant difference in the oxidative capacity of muscle of
c-Cbl-/- mice compared to wild type controls. Furthermore, in high fat fed animals there was an equivalent
increase in oxidative capacity in muscle from knock out and wild type animals (Molero et al Casitas b-Lineage
Lymphoma-Deficient Mice Are Protected Against High-Fat Diet-Induced Obesity and Insulin Resistance.
Diabetes 55:708-15, 2006), 4. Domains in c-Cbl. Considerable progress has been made on this aim. We have
shown that knock in animals in which the Ubiquitin ligase domain in Cbl has been disarmed have a phenotype
resembling the knock out animals. This provides compelling evidence that the phenotype we have observed
relies to a great extent on the ubiquitinylation function of this protein. In combination with the tissue specific
knock out experiments (Aim 1) this should provide important information for target identification. This work
has now been published.
Expected future outcomes:
Once conditional mice have been received we will be in a strong position to map the tissue specificity for the cCbl metabolic phenotype by creating adipose tissue, muscle, liver and brain specific c-Cbl knock out mice.
Name of contact:
David James
Email/Phone no. of contact:
d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325646
Start Year: 2005
CIA Name: Dr Alexander Swarbrick
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Transgenesis
Total funding: $335,857
Title of research award:
The role of ID-family HLH proteins in breast cancerThe role of ID-family HLH proteins in breast cancer
Lay Description (from application):
Not Available
Research achievements (from final report):
A better understanding of the genes mutated in cancer will lead to improvements in our ability to diagnose and
treat cancer. My research focusses on identifying the genes driving the develoment of cancer and its ultimate
spread, or metastasis, through the body. During my tenure as a CJ Martin fellow, I have made two significant
discoveries. In the first, I have shown that the the gene Id1 controls breast cancer growth. I developed a mouse
model for breast cancer and showed that over-production of Id1 in the breast led to the development of
aggressive breast cancers, with a high propensity to metastasise to the lung and lymph node. Inactivation of Id1
in a tumour caused the tumour to enter a state of senescence, or permanent 'sleep'. Targeting the genetic
pathways controling senescence may be a valuable approach in the treatment of cancer, particularly metastatic
disease., In my second discovery, I identified a microRNA that controls the p53 tumour suppressor.
microRNAs are new 'genes' that act in a completely novel way, but may be very important in normal
development and cancer. We have gone on to show that we can dramatically kill cancer cells by preventing
them from producing this microRNA.
Expected future outcomes:
The role of Id1 has now become a focus of my laboratory and we are currently investigating the role of Id1 in
human cancers. We are determining whether Id1 may be a valuable prognostic factor or therapeutic target in
breast cancer. Similarly, we are determining whether the microRNA identified in my research may ultimately
be a therapauetic target in certain cancers
Name of contact:
Alex Swarbrick
Email/Phone no. of contact:
a.swarbrick@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 358302
Start Year: 2005
CIA Name: Prof Jonathan Sprent
End Year: 2010
Admin Inst: Garvan Institute of Medical Research Grant Type: Established Career Fellowships
Main RFCD: Immunology not elsewhere classified
Total funding: $2,198,356
Title of research award:
Burnet AwardBurnet Award
Lay Description (from application):
Not Available
Research achievements (from final report):
This grant was very useful in enabling me to return to Australia after 30 years of research in the USA and start
up a research group in Sydney at the Garvan Institute.. My group in Sydney has been highly productive and has
generated many good papers in high-quality journals and invitations for me and my postdocs to speak at
multiple national and international meetings. My group is now well supported with NHMRC grants.
Expected future outcomes:
I expect my group to continue to perform well and provide further insights on the structure and function of the
immune system and develop new methods to cure cancer and autoimmune disease and promote organ
transplantation.
Name of contact:
Jonathan Sprent
Email/Phone no. of contact:
j.sprent@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 376008
Start Year: 2006
CIA Name: Prof David James
End Year: 2008
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $505,523
Title of research award:
The Role of AS160 in Insulin ActionThe Role of AS160 in Insulin Action
Lay Description (from application):
Obesity and diabetes are increasing in our community at an alarming rate. When one considers that Diabetes is
a major cause of heart disease, stroke and kidney disease these diseases represent one of the most threatening
for the future health of our nation. At the heart of these diseases is a disorder known as insulin resistance, or
the inability of insulin to function correctly. The explosion in biological outcomes over the past decade has
brought us closer than ever before to solving some of the key questions associated with this problem. This
proposal represents an exciting step forward in this area because our recent research combined with
information from our international colleagues have led us to propose a new concept concerning the mechanism
of insulin action. In this proposal we have formulated a series of molecular experiments to test this hypothesis
which if correct will both change the way we think about this problem and provide new prospects for
therapeutic design.
Research achievements (from final report):
This research has enhanced our understanding of how insulin regulates one of its fundamental steps namely the
import of glucose into muscle and fat cells. This step is considered to be one of the most important in
determining the removal of glucose from the bloodstream after a meal and indeed it becomes disrupted in
individuals who are at risk of developing type 2 diabetes. Over the period of the award we have identified
essential elements of how the protein AS160/TBC1D4 and its family members work in fat cells. AS160 is a
RabGAP that is phosphorylated by Akt. We have made the following achievements:, 1. Identified two Rabs
that specifically bind to AS160, 2. Established molecular mechanisms for AS160 dimerisation, 3. Developed
methods to show that phosphorylation and 14-3-3 binding per se are key to the function of AS160 in response
to insulin, 4. Performed systems analysis of AS160 combined with other key Akt substrstes to show that
AS160 is phosphorylated by Akt at the plasma membrane., 5. Used mass spectrometry to identify novel AS160
binding partners. , In a separate body of work we have begun to study the role of other TBC family proteins in
insulin action. Specifically we have found that another protein TBC1D13 binds to Rab10 and when over
expressed in adipocytes profoundly inhibits insulin dependent GLUT4 trafficking. , These studies have
provided novel insights into this important biological process.
Expected future outcomes:
Mutations in TBC1D4 and a related protein TBC1D1 have recently been identified in families with obesity and
Type 2 diabetes. However, the mechanism for this is not yet known. Our work will provide a deeper
understanding of this linkage and as to how the regulation of glucose transport in muscle and fat cells is so
closely linked to whole body energy homeostatsis and metabolism.
Name of contact:
Jacky Stoeckli
Email/Phone no. of contact:
j.stoeckli@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402725
Start Year: 2007
CIA Name: Prof Jonathan Sprent
End Year: 2007
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Cellular Immunology
Total funding: $233,867
Title of research award:
Immunoregulation of subsets of memory CD8+ T cellsImmunoregulation of subsets of memory CD8+ T cells
Lay Description (from application):
Information will be sought on the properties of T cells, a class of white blood cells that play a vital role in
combating infectious agents. Using mouse models, subsets of T cells that carry immunological memory will be
studied and assessed for their rate of cell division and dependence on soluble messengers known as cytokines
and other stimuli. The data will provide useful knowledge on the causes of autoimmune diseases (such as
rheumatoid arthritis, type 1 diabetes and lupus) and help in the development of successful second generation
vaccines.
Research achievements (from final report):
Signifiicnt progress was made in determining how immune cells are kept alive in the body through contact with
growth factors (cytokines) and other ligands in the microenvironment of the lymphoid tissues. Two papers have
been submitted on the role of particular cytokines, namely IL-7 and IL-15, in maintaining the survival and
function of the two main subsets of T cells, namely CD4 cell and CD8 cells. Information from these studies
will ultimately lead to the development of new treatments for autoimmune disease and immunodeficiency.
Expected future outcomes:
Continuing studies on the factors controlling the survival and function of T cells and other immune cells will
inevitably lead to improved methods for vaccine design and treatment of various disease of the immune
system.
Name of contact:
Jonathan Sprent
Email/Phone no. of contact:
j.sprent@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427614
Start Year: 2007
CIA Name: Prof Susan Clark
End Year: 2009
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Oncology and Carcinogenesis
Total funding: $539,250
Title of research award:
Long Range Epigenetic Silencing in CancerLong Range Epigenetic Silencing in Cancer
Lay Description (from application):
Epigenetics is a term that describes modification of gene expression without a change to the DNA sequence,
through processes that involve chemical changes to the DNA such as DNA methylation and binding of specific
proteins. It is now well established that epigenetics plays a major role in cancer development, but one of the
important questions still to be resolved is the mechanism that is responsible for epigenetic changes. Our recent
work has uncovered a new mechanism of epigenetic gene silencing in cancer that can effect large chromosomal
regions. We have found that both methylated and unmethylated genes can be silenced by changes to the
pattern of proteins that bind to the DNA in a cancer cell. Our data also indicates that this silencing can be
reversed using epigenetic drugs. This finding represents a new paradigm in epigenetic control and has major
implications not only on cancer diagnostics but also cancer epigenetic therapy. In this grant we propose to
further characterise and understand the mechanism involved in long range epigenetic silencing and to
determine its prevalence in cancer. This proposal will shed light onto the process underlying long range
epigenetic gene silencing in cancer and will provide potential novel targets for cancer detection, prognosis and
therapy.
Research achievements (from final report):
Epigenetics is a term that describes modification of gene expression without a change to the DNA sequence,
through processes that involve chemical changes to the DNA such as DNA methylation and binding of specific
proteins. It is now well established that epigenetics plays a major role in cancer development, but one of the
important questions still to be resolved is the mechanism that is responsible for epigenetic changes. Our work
funded by this project grant has uncovered a new mechanism of epigenetic gene silencing in cancer that can
effect large chromosomal regions. In particular in prostate cancer we have found that contiguous regions in the
genome containing both methylated and unmethylated genes can be silenced by changes to the pattern of
proteins that bind to the DNA in a cancer cell. Interestingly our data also indicates that this cancer specific
silencing can be reversed using epigenetic drugs. This finding represents a new paradigm in epigenetic control
and has major implications not only on cancer diagnostics but also cancer epigenetic therapy.
Expected future outcomes:
Our research will shed light onto the process underlying long range epigenetic gene silencing in cancer and will
provide potential novel targets for cancer detection, prognosis and therapy.
Name of contact:
Prof Susan Clark
Email/Phone no. of contact:
s.clark@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427642
Start Year: 2007
CIA Name: Prof David James
End Year: 2009
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $303,510
Title of research award:
Dissection of Insulin Regulated Phosphorylation in the AdipocyteDissection of Insulin Regulated
Phosphorylation in the Adipocyte
Lay Description (from application):
Obesity and diabetes are increasing at an alarming rate throughout the world. These diseases are part of a
constellation of disorders that includes cardiovascular disease and kidney disease, which are collectively
referred to as the metabolic syndrome. A disorder referred to as insulin resistance is at the heart of the
metabolic syndrome. This represents the inability of insulin to function correctly in target cells like muscle
and fat. In this project we are attempting to undertake a large scale effort to understand the complex circuitry
that gets turned on within cells when they become exposed to insulin. This project involves a collaboration
between the Garvan Institute and the University of New South Wales Mass Spectrometry Facility allowing us
to bring a combination of very sophisticated technologies to bear on this very significant health care problem.
This project will provide major new insights into our understanding of insulin action yielding new possibilities
for therapeutic development.
Research achievements (from final report):
The output of a biological system is an integrated response of numerous finely tuned regulatory events
involving millions of components. Large-scale studies have begun to define the components. The challenge is
to ascertain how they cooperate in a living cell and how they respond to perturbation. The metabolic system is
ideal as it adapts to environmental change and is relevant to many human diseases. Diabetes represents a
disease where this adaptive network becomes disrupted and the body is unable to cope with incoming nutrients
appropriately. The hormone insulin is at the heart of this regulatory circuit. It is secreted every time we eat to
coordinate the distribution of nutrients. One of the major facets of insulin's actions is to change the activity of
intracellular proteins by a modification called phosphorylation. To completely understand how this system
works it is essential to map all of these phoshorylation events. The goal of this proposal was to discover new
insulin regulated phosphoproteins in the hope of better understanding how insulin works. We developed novel
high resolution methods using a technique known as mass spectrometry to identify phosphoproteins. In
addition to identifying many of the known insulin regulated phosphoproteins we were able to identify 4 novel
proteins. We focussed our efforts on one of these known as Edc3 and this led us to unveil a completely new
pathway regulated by insulin. This will have major impact on future work in this area because this pathway
may have a lasting effect on the ability of cells to regulate metabolism.
Expected future outcomes:
Our work has revealed 4 new proteins phosphorylated by insulin. They control RNA repression, autophagy,
DNA methylation and cell movement. This will catalyse many new studies in each of these important areas.
Also we are now using this approach to map even more insulin-regulated events. This will lead to the most
comprehensive insulin regulated phosphomap.
Name of contact:
David James
Email/Phone no. of contact:
d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 427655
Start Year: 2007
CIA Name: A/Pr Andrew Biankin
End Year: 2009
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Gastroenterology
Total funding: $543,302
Title of research award:
Retinoids in Pancreatic Cancer.Retinoids in Pancreatic Cancer.
Lay Description (from application):
Pancreatic Cancer is the fourth leading cause of cancer death in men and women in Western societies. Nothing,
apart from surgery in a small proportion of individuals gives any hope. The identification of novel treatment
strategies in the modern era necessitates a rational scientific approach, where an understanding of the molecular
mechanisms involved in the evolution of cancer underpins the development of such strategies in an efficient
manner. Retinoids are derivatives of Vitamin A, and have been used extremely successfully in the treatment of
some leukaemias. Unfortunately, retinoids have not worked as well in other cancers. We have identified an
important role for abnormal retinoid function in the evolution of pancreatic cancer, which may be responsible
for the lack of effective response to retinoid treatment. This project focuses on identifying if these
abnormalities in retinoid function can be reversed with adding specific pharmaceuticals so that retinoid based
therapies will be effective in pancreatic cancer.
Research achievements (from final report):
The overall aim was to determine the role of CRBP1 in the development of pancreatic cancer (PC) and identify
novel strategies aimed at using demethylating agents and/or HDAC inhibitors to potentially restore sensitivity
to retinoid based therapies., We demonstrated that loss, or downregulation of CRBP1 expression (a key
component of RA signalling) occurs in 70% of human PC. This is an early event in the development of PC as
loss of CRBP1 expression occurred in pancreatic intraepithelial neoplasia (PanIN), the precursor lesions of PC
and explored its functional role in in vitro culture., In cancers that demonstrated loss, or downregulation of
CRBP1, 30% demonstrated methylation of the CRBP1 promoter region based on bisulphite DNA sequencing
and Methylation Specific PCR (MSP). Treatment of MiaPaCa-2 cells (CRBP1 promoter methylation on MSP)
with the demethylating agent 5-AZA in combination with the histone deacetylase inhibitor TSA resulted in
expression of CRBP1 and cell cycle arrest. , Examination of CRBP1 knockout mice did not reveal a pancreatic
phenotype. GEM models of pancreatic cancer were crossed with reporter mice (RARE-LacZ) which act as a
readout of RA signalling activity and showed absence of RA signalling. Interestingly, when pancreatic injury
was induced in reporter mice, there was marked upregulation of RA signalling, suggesting that RA signalling
plays a role in pancreatic regeneration., A manuscripts describing some of these findings was published in
PLoS ONE with another currently under review. In addition, the role of downstream targets of RA signalling
published in Gastroenterology (IF 11.67).
Expected future outcomes:
Currently, downstream targets of retinoid signalling are being tested in clinical trials as biomarkers of
prognosis and therapeutic responsiveness. Further works is being performed with reagard to the role of retinoid
signalling in pancreatic injury and regenerations and contribution to early pancreatic carcinogenesis.
Name of contact:
Prof Andrew Biankin
Email/Phone no. of contact:
a.biankin@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481307
Start Year: 2008
CIA Name: Prof Elizabeth Musgrove
End Year: 2010
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Oncology and Carcinogenesis
Total funding: $328,195
Title of research award:
Role of cyclin E2 in hormone-responsive breast cancerRole of cyclin E2 in hormone-responsive breast cancer
Lay Description (from application):
The female hormone estrogen stimulates the growth of breast cancers by promoting cell reproduction. We have
found that cyclin E2, which is part of the machinery that controls cell reproduction, responds to estrogen. Since
abnormally high levels of cyclin E2 are linked with earlier relapse in breast cancer, we wish to understand what
role it plays in estrogen action and in breast cancer, how its levels are controlled, and whether too much cyclin
E2 interferes with drugs that block estrogen action
Research achievements (from final report):
This project addressed the function and regulation of the cell cycle regulator cyclin E2 in breast cancer. We
discovered that cyclin E2 gene expression is strongly responsive to treatment with the hormone estrogen, an
important stimulator of breast cancer cell proliferation. In work funded by this project grant we have now
shown that without cyclin E2, estrogen cannot promote cell division, that cyclin E2 overexpression dampens
the response of breast cancer cells to antiestrogens, and dissected the mechanisms for these effects. The closely
related protein cyclin E1 is also important in estrogen/antiestrogen action, but is regulated by different
mechanisms and has a distinct mechanism of action. We have also discovered that overexpression of cyclin E2
interferes with the process of cell division, a characteristic of cancer-promoting genes, and does so to a greater
degree than cyclin E1. These two proteins were previously regarded as interchangeable but our work points to
differences between them that may explain why they are deregulated in different subtypes of breast cancer.
Expected future outcomes:
Our work highlights an association between cyclin E2 overexpression and poor response to endocrine therapies
targeted at estrogen signaling. We are currently testing whether drugs that inhibit cyclin E2-associated kinases
might be effective in endocrine-resistant breast cancer.
Name of contact:
Professor Liz Musgrove
Email/Phone no. of contact:
e.musgrove@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481310
Start Year: 2008
CIA Name: Prof Christopher Ormandy
End Year: 2012
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Research Fellowships
Main RFCD: Endocrinology
Total funding: $617,879
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Discovery and modelling of the processes of hormone induced mammary gland development and
carcinogenesis.
Research achievements (from final report):
This Fellowship enabled the discovery of the key role played by Elf5 in the normal development of the breast
and in breast cancer. In normal development Elf5 is a "master regulator" responsible for specifying the
production of the cell lineage that forms during pregnancy and produces milk during lactation. Forced
experssion of Elf5 causes the production of milk in virgin animals. To do this Elf5 supresses the proliferation
of the estrogen receptor positive hormone sensing cells, and this activity continues in breast cancer. High Elf5
expression causes the formation of estrogen receptor negative basal breast cancer. Remarkably when estrogen
receptor positive breast cancer becomes resistant to antiestrogn therapy these cancers re express Elf5 at high
levels.
Expected future outcomes:
We are examining the relationship between Elf5 and key estrogen response genes such as FoxA1. We are also
examining the ability of Elf5 to produce metatstasis.
Name of contact:
Chris Ormandy
Email/Phone no. of contact:
c.ormandy@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481345
Start Year: 2008
CIA Name: A/Pr Christopher Ormandy
End Year: 2011
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $720,516
Title of research award:
ELF5 integrates prolactin and progestin control of mammary gland development via regulation of progenitor
cells.ELF5 integrates prolactin and progestin control of mammary gland development via regulation of
progenitor cells.
Lay Description (from application):
Elf5 may act as a master-regulator of mammary cell growth during pregnancy. We will demonstrate that Elf5
can replace the requirement for prolactin and progesterone to trigger mammary development and we will
determine the stem or progenitor cells Elf5 acts on. Finally we will apply this knowledge to breast cancer cell
lines to discover what role Elf5 plays in breast cancer. These experiments have the potential to establish Elf5 as
a new therapeutic target for the treatment of breast cancer.
Research achievements (from final report):
We showed that prolactin and progesterone regulate mammary gland development via paracrine signals sent to
mammary progenitor cells. The chief paracrine regulator was RANKL. This work has openned the way for the
application of existing drugs targetting RANKL to breast cancer.
Expected future outcomes:
We will publish an additional manuscript showing that RANKL provides a mechnaism by which steroid
hormone positive cells can influence steroid hormone receptor negative cells within the mammary gland.
Name of contact:
Chris Ormandy
Email/Phone no. of contact:
c.ormandy@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481347
Start Year: 2008
CIA Name: Prof Susan Clark
End Year: 2010
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Oncology and Carcinogenesis
Total funding: $745,357
Title of research award:
Epigenetic Silencing of Large Chromosomal Regions in Prostate Cancer.Epigenetic Silencing of Large
Chromosomal Regions in Prostate Cancer.
Lay Description (from application):
Epigenetics is a term that desribes modification of gene expression without a change to the DNA sequence
through processes that involve chemical change to the DNA such as methylation. In this grant we will further
characterise and understand the mechanism involved in long range epigenetic silencing and determine its
prevalence in prostate cancer. This study will provide potential novel targets for prostate cancer detection,
prognosis and therapy.
Research achievements (from final report):
We created an integrated prostate cancer epigenome map, and showed for the first time that many regions of
the cancer genome are commonly inactivated through changes to the epigenome, that is the layers of chemical
information above the genome. Throughout the cancer genome we found that adjacent genes are frequently
changed to the same epigenetic silencing state, by re-enforcement and/or replacement of repressive histone and
DNA methylation marks. Lastly, we found that concordant hypermethylated regions are linked with prostate
cancer progression.
Expected future outcomes:
This study has sparked a new area of research namely the epigenetic study of how the genome is regulated in
domains and how these domains are deregulated in cancer .
Name of contact:
Susan Clark
Email/Phone no. of contact:
s.clark@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481378
Start Year: 2008
CIA Name: Dr Sandra Biankin
End Year: 2011
Admin Inst: Garvan Institute of Medical Research Grant Type: Early Career Fellowships (Australia)
Main RFCD: Pathology
Total funding: $115,981
Title of research award:
Therapeutic targeting of the Hedgehog signaling pathway in premalignant lesions of the breast.Therapeutic
targeting of the Hedgehog signaling pathway in premalignant lesions of the breast.
Lay Description (from application):
Breast screening has been successful in reducing deaths from breast cancer. Unfortunately it also detects
increasing numbers of precancerous changes. Treatment of these changes is often aggressive, using surgery and
radiotherapy. However we are unable to predict exactly which of the changes we need to treat. We aim to
better understand the changes involved in this progression and try to block them using new drugs.
Research achievements (from final report):
Research supported by this training fellowship has shown for the first time that abnormal Hedgehog Pathway
signalling is an early event in breast cancer and is associated with the aggressive basal-like subtype and with a
poor prognosis. We have also shown that inhibition of the pathway in mouse models of breast cancer decreases
tumour size and reduces metastatic spread. Other work undertaken in this Fellowship has shown that aberrent
expression of beta catenin in breast cancer is a marker of poor prognosis and that overexpression of Notch1
receptor is an early event in breast cancer development and is associated with HER2 breast cancer. Other
studies have contributed to identifying a poor prognosis group in ER positive breast cancer.
Expected future outcomes:
Based on these exciting results we are developing a clinical trial to test Hh pathway inhibition in triple negative
breast cancer.
Name of contact:
Sandra O'Toole
Email/Phone no. of contact:
s.otoole@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481389
Start Year: 2008
CIA Name: Prof Charles Mackay
End Year: 2009
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Development Grants
Main RFCD: Clinical Pharmacology and Therapeutics
Total funding: $174,867
Title of research award:
Development of anti-CXCR2 monoclonal antibodies for tumour therapyDevelopment of anti-CXCR2
monoclonal antibodies for tumour therapy
Lay Description (from application):
New therapies to treat cancers and inflammatory diseases are urgently required. Our aim is to develop a new
treatment for cancer and inflammation, by blocking the chemokine receptor CXCR2 which is central to
angiogenesis (blood vessel growth) and inflammation. We have produced a highly effective monoclonal
antibody (mAb) inhibitor of CXCR2, which is suitable for preclinical and clinical development. The project
aims to examine the efficacy of this mAb in mouse tumour models and inflammation.
Research achievements (from final report):
Unfortunately we were unable to show involvement of an important role for chemokine receptors in tumor
development. mAb based drugs against chemokine recptors have promise in inflammation, but their role in
cancer is yet to be fully validated.
Expected future outcomes:
Anti-chemokine receptor mAbs may have much more utility in other conditions such as fibrosis, and future
effort will be directed in this line of work.
Name of contact:
Charles Mackay
Email/Phone no. of contact:
c.mackay@me.com
NHMRC Research Achievements - SUMMARY
Grant ID: 516792
Start Year: 2008
CIA Name: Dr Samantha Oakes
End Year: 2013
Admin Inst: Garvan Institute of Medical Research Grant Type: Early Career Fellowships (Australia)
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $470,347
Title of research award:
Isolation and characterisation of novel progenitor cells in the mammary epithelium and their role during
carcinogenesis.Isolation and characterisation of novel progenitor cells in the mammary epithelium and their
role during carcinogenesis.
Lay Description (from application):
Stem and progenitor cells in the breast are the immature cells from which mature cells are derived. Their are
long-lived, resistant to death and can produce multiple types of mature cells, implicating them as cells from
which breast cancer may originate. We aim to search for novel cell surface markers that define the progenitor
cells in the mouse mammary gland. The data gathered from this project may facilitate the development of
targeted therapies to the cells of origin in breast cancer.
Research achievements (from final report):
Triple negative cancers are difficult to treat and have the worst prognosis. The small molecule inhibitor ABT737 reactivates cell death by binding to and inhibiting a pro-survival protein BCL-2. We created a pre-clinical
model of triple negative breast cancer in mice and tested whether ABT-737 was an effective treatment strategy
in breast cancer. We showed that ABT-737 enhanced the efficacy of conventional chemotherapy in breast
tumours that expressed high levels of the protein BCL-2. Our research proves the efficacy of a specific BCL-2
inhibitor such as ABT-199 (a derivative of ABT-737) in the treatment of breast cancer. We further provide the
proof of principle for the establishment of clinical trials that investigate the efficacy ABT-199 in combination
with conventional chemotherapy for the treatment of BCL-2 expresing breast cancers.
Expected future outcomes:
Recently a specific inhibitor of BCL-2 was developed (ABT-199) and is currently in phase I/II clinical trials
for haematologic malignancies.In 2013, the CIA's parent laboratory received a large National Breast Cancer
Foundation grant to further investigate the effictiveness of this strategy in the clinic.This fellowship funding
has also enabled me to establish my independent career at the Garvan
Name of contact:
Samantha Richelle OakesDr Samantha Oakes
Email/Phone no. of contact:
s.oakes@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 535903
Start Year: 2009
CIA Name: Prof Roger Daly
End Year: 2013
Admin Inst: Garvan Institute of Medical Research Grant Type: Programs
Main RFCD: Oncology and Carcinogenesis
Total funding: $11,762,117
Title of research award:
Molecular markers of phenotype, therapeutic responsiveness and prognosis in human cancers.Molecular
markers of phenotype, therapeutic responsiveness and prognosis in human cancers.
Lay Description (from application):
This proposal aims to identify molecular markers that can be used to classify subtypes of particular cancers
according to their prognosis and response to therapy. This will optimise selection of patients for the most
appropriate treatment and lead to the development of new therapeutic strategies.
Research achievements (from final report):
Over the course of this Program Grant, major achievements were made in four areas, each directly relating to
specific aims of the grant. First, we made key discoveries regarding the mechanistic basis of phenotype
specification in human cancers. These included: the identification of the transcription factor Elf5 as a key
regulator of the gene expression patterns that define particular breast cancer subtypes; and through large-scale
cancer genome sequencing, determination that mutations in axon guidance pathway genes characterize
pancreatic cancer. Second, we identified key markers of particular cancer phenotypic subtypes, including Hh
(basal breast cancer) and p53 (luminal B breast cancer). Third, we characterized several novel markers of
prognosis and therapeutic responsiveness, including S100A2, which predicts response to pancreatectomy in
pancreatic cancer, and PUMA, which predicts tamoxifen responsiveness in breast cancer. Fourth, we have
identified and validated novel phenotype-specific therapeutic targets, including FAK for docetaxel resistant
prostate cancer. This work has led to an improved understanding of several human cancers at a phenotypic and
mechanistic level and has identified potential biomarkers and therapeutic targets that can be exploited in order
to improve clinical management of breast, prostate and pancreatic cancer.
Expected future outcomes:
Further development of our research findings will lead to a comprehensive understanding of phenotype
specification in human cancer and through biomarker and therapeutic target validation and clinical
implementation, improved management of breast, prostate and pancreatic cancer.
Name of contact:
Professor Roger Daly
Email/Phone no. of contact:
roger.daly@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 535947
Start Year: 2009
CIA Name: Dr Alexander Swarbrick
End Year: 2012
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Oncology and Carcinogenesis
Total funding: $606,812
Title of research award:
Dissecting the function of the Hedgehog-Patched pathway in breast cancer progressionDissecting the function
of the Hedgehog-Patched pathway in breast cancer progression
Lay Description (from application):
There have been significant improvements in survival from breast cancer, particularly due to specialised
treatments that target faulty pathways in the growth of cancer cells. One newly described, aggressive type of
breast cancer called basal-like breast cancer lacks specialised treatment. We will determine whether the
'Hedgehog' signalling pathway is a suitable target for basal breast cancer therapy.
Research achievements (from final report):
Significant improvements in outcome for women with basal-like breast cancer will likely depend on the
development of targeted therapies, as evidenced by the dramatic improvement in the treatment of HER2
amplified breast cancers made possible by the development of Trastuzamab. Our research showed that the
Hedgehog signalling pathway is a promising potential target for therapy in the basal-like breast cancer subtype.
In a series of interlocking specific aims, we showed a subsets of poor-prognosis basal breast cancers express
high levels of Hedgehog. Furthermore, we used mouse models of disease to show that inhibition of Hedgehog
signaling can lad to marked reductions in tumor growth and metastasis. Given the success of monoclonal
therapies in a range of malignancies in recent years, and the passage of several small molecule Hh inhibitors
through Phase 1/2 clinical trials for other diseases, we contend that the ultimate translational impact of this
work is the potential to use an antibody- or small molecule-based strategy to block SHH ligand activity as
therapy for basal breast cancer.
Expected future outcomes:
We have received additional funding to explore the clinical feasibility of targeting the Hedgehog pathway in
breast cancer. Should this be successful, women with high risk basal breast cancer may receive drugs targeting
Hedgehog as part of the treatment.
Name of contact:
Dr Alex Swarbrick
Email/Phone no. of contact:
a.swarbrick@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 596822
Start Year: 2010
CIA Name: Prof Robert Brink
End Year: 2012
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Haematological Tumours
Total funding: $439,396
Title of research award:
Regulation of B lymphocyte survival and tumourigenesis by the TRAF2-TRAF3-cIAP signaling
complexRegulation of B lymphocyte survival and tumourigenesis by the TRAF2-TRAF3-cIAP signaling
complex
Lay Description (from application):
A major contributing factor in the development of cancer is the loss of the normal controls that regulate cell
survival. We have identified a group of proteins that control the survival of B cells, the white blood cells
responsible for producing the antibodies that fight infections. In this project we will investigate the mechanisms
by which these proteins function and how inactivation of their functions can lead to multiple myeloma, an
aggressive cancer of antibody producing cells.
Research achievements (from final report):
* design and construction of a new method for delevering and expressing genes in the mouse - published in a
paper in The Journal of Immunological Methods in 2010* use of this vector to determine how the TRAF2
protein controls the survival and function of B cells, white blood cells that ultimately give rise to the antibody
producing "plasma" cells* demosntration that the TRAF3, TRAF3 and cIAP proteins collaborate to control the
survival and function of B cells - the last two findings published together in a paper in the journal Blood in
2011* demonstrated that the absence of TRAF3 from plasma cells results ineir accumulation in the bone
marrow resembling the "amouldering" form of multiple myeloma, a cancer of bone marrow plasma cells* also
showed that the absence of TRAF3 results in the accumulation of B cells that resmble the putative stem cell for
multiple myeloma, the "memory" B cell* determined that TRAF3-deficient plasma cells have a gene signature
characteristic of a proliferating cell, consistent with them adopting cancer-like characteristsics associated with
multiple myeloma
Expected future outcomes:
development of a model of a mouse model multiple myeloma using TRAF3-deficient B cells/plasma cells*
development of novel strategies for treating myeloma based of information from this model* testing of antimyeloma strategies in this model
Name of contact:
A/Prof Robert Brink
Email/Phone no. of contact:
r.brink@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 596836
Start Year: 2010
CIA Name: A/Pr Cecile King
End Year: 2012
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Humoural Immunology and Immunochemistry
Total funding: $390,505
Title of research award:
The role of linked cytokines in T helper cell differentiationThe role of linked cytokines in T helper cell
differentiation
Lay Description (from application):
An important class of T cells known as T Follicular Helper cells (TFH) orchestrate the immune response so
that we can produce antibodies to fight infection. The novel finding that our Lab made last year is that the
molecule interleukin 21 (IL-21) is a growth factor for TFH. The findings we have made thus far could be used
in a number of ways. For eg, IL-21could be used to expand numbers of TFH, using them to boost vaccination
or natural defences against viruses, bacteria and tumour cells.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
Cecile King
Email/Phone no. of contact:
c.king@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 596868
Start Year: 2010
CIA Name: Ms Michelle Linterman
End Year: 2013
Admin Inst: Garvan Institute of Medical Research Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Cellular Immunology
Total funding: $217,806
Title of research award:
The role of microRNAs in T follicular helper cell mediated humoral immunity and autoimmunity.The role of
microRNAs in T follicular helper cell mediated humoral immunity and autoimmunity.
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
To neutralise threats from viruses and bacteria the immune system generates antibodies that interact with
pathogens and prevent them from establishing an infection. While this process is highly effective it is not
infallible. In some people the immune system can generate antibodies that bind components of the body it is
designed to protect, this can lead to autoimmunity. This research proposal aimed to understand how a particular
type of immune reaction, the germinal centre, is controlled to avoid production of auto-antibodies. This
research had two main focal points. 1) The role of the costimulatory molecule CD28 as targetting CD28 is used
to treat autoimmune and inflammatory disease. Here, we showed that CD28 is required to maintain the
germinal centre response and this may help to explain why blocking CD28 is an effective therapeutic in
autoimmune disease. 2) How the B cell depleting therapeutic rituximab affects the germinal centre response in
humans. We show that rituximab depletes the germinal centre B cells, but that germinal centre T cell remain,
this has implications for how rituximab is used to treat autoimmune disease. Together, this research programme
has advanced our understanding of the germinal centre, particularly with respect to therapeutic targets for
autoimmunity.
Expected future outcomes:
A better understanding of how T follicular helper cells are maintained. This may have implications for
targetting these cells theraputically in autoimmunity.
Name of contact:
Michelle Linterman
Email/Phone no. of contact:
michelle.linterman@babraham.ac.uk
NHMRC Research Achievements - SUMMARY
Grant ID: 596869
Start Year: 2010
CIA Name: Dr Martijn Bijker
End Year: 2011
Admin Inst: Garvan Institute of Medical Research Grant Type: Early Career Fellowships (Australia)
Main RFCD: Tumour Immunology
Total funding: $92,580
Title of research award:
NPY and its Y-receptors as new targets to enhance T cell-mediated cancer therapy.NPY and its Y-receptors as
new targets to enhance T cell-mediated cancer therapy.
Lay Description (from application):
The immune system is capable of clearing cancers, but it requires large numbers of highly activated immune
cells to achieve this. Neuropeptides are able to inhibit the immune response and can thereby prevent that the
immune system can eradicate the cancer. This study aims to understand the inhibitory effects of Neuropeptides
on the immune system. This knowledge will provide important information on how we can further improve
anti-cancer treatments.
Research achievements (from final report):
It is known for a long time that stress has a negative impact on the immune system making the body more
prone for bacterial and viral infection, but it also increases the risk for cancer. With this project we are
incorporating this knowledge that stress molecules can inhibit the immune response and could directly inhibit
the immune response against cancer. By targeted intervention we could prevent the inhibition of the immune
system by these stress hormones, to thereby boost the immune response against the tumours and induce longterm protection.
Expected future outcomes:
Potential patent application
Name of contact:
Dr. Martijn Bijker
Email/Phone no. of contact:
martijnbijker@yahoo.com
NHMRC Research Achievements - SUMMARY
Grant ID: 1004632
Start Year: 2011
CIA Name: Dr Tri Phan
End Year: 2013
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Tumour Immunology
Total funding: $451,011
Title of research award:
The role of subcapsular sinus macrophages in lymph node metastasesThe role of subcapsular sinus
macrophages in lymph node metastases
Lay Description (from application):
This project tackles the problem of lymph node metastases using complementary studies in mouse models and
human patients with melanoma. It takes the novel approach of examining the local geographical factors in the
lymph node and focusses on a rare cell called the subcapsular sinus macrophage that may be a critical
determinant of the clinical outcome. This will result in innovative strategies for primary prevention of not only
melanoma but other cancer cell metastases.
Research achievements (from final report):
We have discovered that subcapsular sinus (SCS) macrophages are extremely "sticky" and can act like flypaper to trap infectious agents and cancer cells draining in the lymph node. This also means that they are quite
difficult to isolate from the lymph node with a high level of purity and we have made progress towards this by
characterising the contaminating cells that stick to the SCS macrophages during cell isolation. This reinforces
the need to study interactions between cancer cells and SCS macrophages in live animals. We have therefore
successfully developed a number of new tools and techniques that make it now possible to do just that. This
includes a method for fluorescently tagging cells ("non-linear optical highlighting") in live animals for tracking
cell fate by intravital two-photon microscopy. We have also cloned and retrovirally transfected the fluorescent
optical highlighter Kikume into cancer cells. We have also been also to classify and grade the microanatomical
location of melanoma micrometastases and correlate them with risk of distant metastases and survival to
confirm the clinical significance. Taken together, these results suggest that localised therapy to target SCS
macrophages and their interactions with cancer cells, for example by making them less "sticky", may impact on
the development of metastases and we are currently pursuing these lines of research.
Expected future outcomes:
Our data paves the way for further studies investigating the molecular interactions and regulation of SCS
macrophages and how they interact with cancer cells. This is a promising line of research to develop targeted
therapies to prevent metastases.
Name of contact:
Tri Giang Phan
Email/Phone no. of contact:
t.phan@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1013515
Start Year: 2012
CIA Name: Dr Kendle Maslowski
End Year: 2014
Admin Inst: Garvan Institute of Medical Research Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Innate Immunity
Total funding: $242,697
Title of research award:
A study of the function of neuronal apoptosis inhibitory proteins (NAIP) in innate immunity.A study of the
function of neuronal apoptosis inhibitory proteins (NAIP) in innate immunity.
Lay Description (from application):
The innate immune system is the first line of defence against infection and cancer. Regulation of the immune
system is extremely important as too little response can lead to severe infections, whilst too much response can
lead to chronic inflammatory disease. This project will examine the role of ‘neuronal apoptosis inhibitory
protein’ in the immune system, which should provide information on regulation of innate immunity, as well as
provide insight to neurodegenerative diseases and cancer.
Research achievements (from final report):
This project analysed the role of 'NAIPs' (Nod-like receptor family apoptosis inhibitory proteins), a family of
duplicated genes, in intestinal immune responses and cancer development. This family of genes are known to
be 'detectors' of intracellular bacteria, including Salmonella, and important for mounting an immune response
against the bacteria. We found NAIPs gene and protein expression was high in the colon epithelium, and
therefore wanted to determine what function NAIPs have there. , , We discovered that NAIPs were required to
protect the colon from tumor development. Most intruingly, NAIPs were required to induce cell death in colon
epithelial cells that were affected by carcinogen (cancer causing agent) exposure, thereby reducing the number
of tumors in response to carcinogen exposure. , , Additionally, we examined the role of NAIPs in intestinal
infection. The biological processes following early infection by Salmonella, a common cause of food
poisoning, is not well understood. In collaboration with W.D. Hardt's group at the ETH in Zurich, we found
that NAIPs were involved in the detection of Salmonella in the hours following infection and were required to
limit the growth of Salmonella by causing expulsion of the infected cells, thereby reducing the level of
infection in mice. ,
These findings will initiate more
research into the mechanisms by which NAIPs control colon epithelial reponses to pathogens and carcinogenic
insults, and whether the two are linked evolutionarily.
Expected future outcomes:
Ongoing work is aiming to understand the underlying cellular mechanisms of tumor suppresion. The
relatedness of pathways involved in pathogen recognition/expulsion and inhibition of cancer development are
also being studied. The studies so far have been in mice, so the relevence of these pathways to human biology
will be investgated.
Name of contact:
Kendle Maslowski
Email/Phone no. of contact:
kendle.maslowski@riken.jp / endlemaslowski@gmail.com
NHMRC Research Achievements - SUMMARY
Grant ID: 102463
Start Year: 2000
CIA Name: Dr Hendrick (Derek) Kennedy
End Year: 2002
Admin Inst: Griffith University
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $200,881
Title of research award:
Characterisation of a new family of proteins involved in cell signalling, RNA metabolism and
cancerCharacterisation of a new family of proteins involved in cell signalling, RNA metabolism and cancer
Lay Description (from application):
We have discovered a novel RNA-binding protein (G3BP-2) that is involved in responding to external signals,
such as growth factors, at the level of gene expression. Other RNA-binding proteins belonging to the same
broad group of proteins are responsible for a host of disease states in mammals including mental retardation,
myotonic dystrophy, Huntington?s disease and cancers. Considering the wealth of knowledge accumulated
that implicates these proteins to human dysfunction surprisingly few of these RNA-binding proteins have been
identified. We have shown that the novel protein discovered in our laboratory is perturbed in cancer and we
are interested in characterising its putative role in cancer. The results established in our laboratory so far would
indicate that generally, G3BP-2 is expressed in normal tissue and it expression changes in some cancers studied
so far. Considering that G3BP-2 lies in a pathway known to be involved in cancer progression it is important
to understand what effects the inappropriate expression of G3BP-2 may have on cancer progression and
survival. This project is designed to characterise what signals the cell uses to control these proteins and in turn
which genes these may effect. In this way we may be able to determine how external signals may effect
tumour progression and on what genes this influence is expressed. It would be hoped that this project would
increase our understanding of cancer and potentially lead to new diagnostic reagents and therapies in the
treatment of cancer.
Research achievements (from final report):
We are hoping that the identification and characterisation of our protein of interest (G3BP) in human breast
cancers will lead to significant developments in an anti-breast cancer therapeutic. The research developed in
this project is only in its initial stages and we still need to look at the feasibility of using our research to
develop an immunotherapy (a concept that we had not considered at the onset of this project and has only been
brought about by this project). In addition, we are exploring the possibility of targeting our protein as a
candidate for drug treatment. This is based on the finding that our protein appears to be related to the
proliferative rate (growth rate) of a tumour. If we can target this protein we may be able to slow or even stop
the growth of a tumour.
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 143557
Start Year: 2001
CIA Name: Dr Stephen Ralph
End Year: 2003
Admin Inst: Griffith University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $227,037
Title of research award:
Regulation of Stat1 activity levels: abnormalities in human melanoma cells resistant to interferon.Regulation of
Stat1 activity levels: abnormalities in human melanoma cells resistant to interferon.
Lay Description (from application):
Melanoma and its treatment continues to be an important health concern in Australia. The interferons comprise
an elaborate system of natural substances produced in the body, one of whose functions is to prevent cancer
cells from developing. The interferons have been widely used to treat human diseases including viral
infections and cancers like malignant melanoma. However, results of recent trials have cast doubt on its
effectiveness. We have found that advanced stage melanoma cells resist the direct anti-cancer effects of
interferons because they have abnormalities in their ability to respond to interferon. We have made good
progress in understanding why the melanoma cells do not respond to the interferons. In particular they show a
deficiency in the activity of protein, Stat1, required to send the interferon signal inside the cells. The current
proposal will allow us to gain a greater understanding of the processes inside cancer cells regulating Stat1
activity and the reasons for its abnormality in interferon resistant cancer cells. This study will help establish an
assay to predict which cancer patients will respond to interferon therapy, saving pateints from unecessary
discomfort and costs. It will also have a broad significance to many human diseases where abnormalities in
interferon signaling occur and will help to bring about ways to produce the necessary changes in cell properties
to overcome the abnormalites, restore the responses and improve the application of interferons to treat
melanoma and perhaps other human diseases as well.
Research achievements (from final report):
We were one of the first research groups to discover that cancer cells like those in melanoma skin cancer often
do not respond to the effects of the interferons, providing an explanantion for why the interferons as a cancer
therapy often fail. The interferons are biological signals used by the immune system to prevent infections and
cancers from arising. Interferons have been approved as drugs by the FDA for use in the treatment of certain
cancers such as melanoma in humans. However, interferon therapy is a very long drawn out therapy with many
side effects. Resistance of cancer cells to interferons has more recently been shown to occur as part of the
progrssion of cancers as they escape our immune system and this observation helps explain why interferon
therapy often does not work in cancer patients. Our early observations showed that melanomas resistant to the
interferons were lacking factors inside cells needed for signalling. When interferons bind to the outer surface of
cancer cells, these signalling factors inside are normally activated and then relay the signal down to the outer
surface of cancer cells, these signalling factors inside are normally activated and then relay the signal down to
the nucleus to bring about the necessary changes such as blocking cell growth as well as helping to remove the
cells from the body. Other reports have since confirmed our findings that cancer cells lack these signalling
factors inside. This observation has been extended by other workers to be part of a widespread phenomenon in
the development of many different types of cancers. The results help to explain why many cancer patients do
not respond to interferon therapy. In the latter part of this project, we focussed our efforts to address why the
interferon resistant cancer cells lack interferon activated signalling factors. This required us to determine how
interferon signalling factors themselves are regulated at the level of their genes. We began defining the
processes involved in their gene regulation until the funding terminated.
Expected future outcomes:
An important aspect of these studies was to be able to define how the genes for the interferon signalling factors
are switched on and off again. We believed that if we could define this process, then we would be able to
predict those cancer patients benefitting from interferon therapy and hence we could develop a useful
diagnostic assay, saving unnecessary suffering.
NHMRC Research Achievements - SUMMARY
Name of contact:
Dr Stephen Ralph
Email/Phone no. of contact:
s.ralph@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 369700
CIA Name: A/Pr Pam McGrath
Admin Inst: Griffith University
Main RFCD: Primary Health Care
Total funding: $665,060
Start Year: 2006
End Year: 2011
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
I established the International Program of Psycho-Social Health Research (IPP-SHR) that provided
international leadership through research, publications, education, media, quarterly review, and podcasting for
the broad umbrella of psycho-social health research. My research program has at its core an exploration of the
human experience of serious illness and is concerned with ensuring appropriate delivery of best practice
psycho-social care throughout all facets of health service delivery. Supported by a range of grants from
competitive, government and industry funding my research explores a range of psycho-social issues including
Indigenous health, palliative care, haematology, bioethics, international medical graduates (IMGs), live donor
renal transplantation, obstetrics, and mental health. At an international level I am conducting and publishing
research in a number of locations (India, New Zealand, and Canada) and have an industry partner with a
commitment to ongoing funding (Leukaemia and Blood Foundation, New Zealand). The program is producing
a high level of output (such as project initiation and completion, publications, conference presentations,
podcasting, quarterly review), and has a strong track record in translating research into practice and policy
(such as the Senate Inquiry into transport and accommodation, the models for both Indigenous and the
haematology palliative care). ,
Expected future outcomes:
The first five years of the SRF was conducted at CQ University. In 2011 I transferred to the Griffith Health
Institute, Griffith University, where my work is supported by a strong health research culture. The vision for
the future is to continue leadership in psycho-social health research.
Name of contact:
Pam Mcgrath
Email/Phone no. of contact:
p.mcgrath@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481962
CIA Name: A/Pr Chuan Xiang Zhou
Admin Inst: Griffith University
Fellowships
Main RFCD: Molecular Evolution
Total funding: $218,669
Start Year: 2008
End Year: 2010
Grant Type: International Exchange Early Career
Title of research award:
Mechanisms of Head and Neck Cancer Progression Role of Matrix Metallopreinase (MMP-2) Using in vitro
and in vivo AnimaMechanisms of Head and Neck Cancer Progression Role of Matrix Metallopreinase (MMP2) Using in vitro and in vivo Anima
Lay Description (from application):
This proposal will assist in improving human health, quality of life and patient lifespan. Head and Neck cancer
is of high prevalence in Australia and China. Cancer patients, often with metastasis to adjacent and distant
organs, including bone at late stages of the disease, suffer from pain, facial nerve paralysis, recurrence and
frequently die under very distressing circumstances. This proposal intends to elucidate the molecular
mechanism of Head and Neck cancer and help come up with better treatments against cancers including
providing a new target for cancer gene therapy.
Research achievements (from final report):
This proposal will assist in improving human health, quality of life and patient lifespan. Head and Neck cancer
is of high prevalence in Australia and China. Cancer patients, often with metastasis to adjacent and distant
organs, including bone at late stages of the disease, suffer from pain, facial nerve paralysis, recurrence and
frequently die under very distressing circumstances. This proposal intends to elucidate the molecular
mechanism of Head and Neck cancer and help come up with better treatments against cancers including
providing a new target for cancer gene therapy.
Expected future outcomes:
This study will provide a valuable molecular and preclinical base to study mechanisms of involvement of
MMP-2 / -9 in the formation of osteoblastic or osteolytic lesions of head and neck cancer. This may lead to the
development of biomarkers for aggressive cancer and treatment strategies for cancer metastasis or recurrence.
Name of contact:
Jin Gao
Email/Phone no. of contact:
j.gao@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 496003
CIA Name: Suzanne Steginga
Admin Inst: Griffith University
Main RFCD: Health Counselling
Total funding: $405,001
Start Year: 2008
End Year: 2012
Grant Type: Career Development Fellowships
Title of research award:
Randomised controlled trial of early intervention to improve sexual and couple functioning after prostate
cancerRandomised controlled trial of early intervention to improve sexual and couple functioning after prostate
cancer
Lay Description (from application):
Treatment for localised prostate cancer has a long term negative impact on the sexuality, quality of life, and
relationship quality of Australian men and their intimate partners. This study will trial a remote access couples
based sexuality intervention for this patient and carer group that has potential for broader translation into
community and acute health care settings. This approach will also have broader application for chronic disease
self management for other health conditions.
Research achievements (from final report):
The career objectives for this Fellowship included developing: a comprehensive program of prostate cancer
research; mechanisms for translation of research into practice; enhanced research collaborations; processes for
integration of social impact markers of merit with traditional academic frameworks; a new program of research
in evidence-based psychosocial intervention for cancer patients. These objectives were achieved and perhaps
best marked by my research outputs. Since 2006 I have attracted $4,730,244 in research funding as Chief Lead
Investigator with a further $3,555,827 as Co-Investigator : a total over the past five years of $8,286,071. I have
published/in press 98 peer review manuscripts; 3 book chapters; 31 published abstracts. In my fields of
psychology multi disciplinary and social sciences biomedical my citation rates are more than three times the
world average; and twice the world average in social sciences interdisciplinary and psychology
(ThomsonReuters Feb 2012; WoS 1998-2010). I have 962 citations; h-index of 17 and C-Index of 2.4 that
relative to opportunity is outstanding. In 2011 I received the Clinical Research Award in the Australian Society
for Medical Research (Qld) Health and Medical Research Awards. I now have collaborations with Temple Uni
USA; Memorial Sloane-Kettering NY; Uni of Virginia; MD Andersen Cancer Centre, Houston; and several
leading Australian universities., In conclusion I have now established a significant program of internationally
leading psychosocial intervention research for people affected by cancer and in doing so built a body of
knowledge that is currently, and will further in the future, influence health care services in this focus area.
Expected future outcomes:
My research with people affected by cancer has produced rigorously developed psychosocial intervention
programs that are now ready for large scale translational research using remote technologies. Work on this is
advancing with key non-government agencies such as the Cancer Council Queensland and the Prostate Cancer
Foundation of Australia.
Name of contact:
Prof Suzanne Chambers
Email/Phone no. of contact:
suzanne.chambers@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 496714
CIA Name: Dr Louisa Gordon
Admin Inst: Griffith University
Main RFCD: Health Economics
Total funding: $301,765
Start Year: 2008
End Year: 2013
Grant Type: Early Career Fellowships (Australia)
Title of research award:
The economic impact of managing gastro-oesophageal reflux disease, Barretts oesophagus and oesophageal
cancer.The economic impact of managing gastro-oesophageal reflux disease, Barretts oesophagus and
oesophageal cancer.
Lay Description (from application):
Cancer of the oesophagus is a deadly disease with less than 20% of patients expected to live beyond one year
after diagnosis. Oesophageal cancer is strongly linked to acid reflux and obesity. This study will look at the
economic impact of treating patients for oesophageal cancer and associated precursor conditions and explore
the cost-effectiveness of potential screening options for individuals at high-risk.
Research achievements (from final report):
4 peer-reviewed research articles in good clinical journals presenting the outputs of the research topic (one is
under review), 20 additional research articles published on mostly cancer populations in public health, cancer
and policy journasl, 2 conference presentations.
Expected future outcomes:
Invited to contribute to a special edition of Cost effectiveness issues in gastrointestinal practice -Volume 27,
2013 in the journal Best Practice & Research Clinical Gastroenterology (submitted and under review)- Invited
to contribute to the Cancer CouncilAustralia Barrett's Oesophagus Guidelines - reviewing the costeffectiveness of surveillance strategies.
Name of contact:
Louisa Gordon
Email/Phone no. of contact:
louisa.gordon@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 631402
Start Year: 2010
CIA Name: A/Pr Nigel McMillan
End Year: 2013
Admin Inst: Griffith University
Grant Type: NHMRC Project Grants
Main RFCD: Cancer Therapy (excl. Chemotherapy and Radiation Therapy)
Total funding: $570,877
Title of research award:
RNA interference and the Immune SystemRNA interference and the Immune System
Lay Description (from application):
RNA interference is a newly discovered means by which we are able to turn off cancer-causing genes with high
precision. However, it is difficult to get the drug to every cancer cell. Therefore we are designing and testing
new RNA interference molecules that are able to alert the immune system to the presence of the cancer thus
causing its elimination. This will prove to be a more effective cancer treatment than current therapies.
Research achievements (from final report):
Our current cancer treatments are all rather non-specific, attacking cells that grow quickly ratehr than the
cancers themselves. A new therapy called gene scilening has been developed that attacks the cancers by turning
off cancer causing genes. The aim of this work was to improve gene scilencing by investigate the mechanisms
by which the immune system could also recognise cancers following gene scilencing. During this grant we
discovered how gene silecing can be designed to improve the the recognition of cancers byt heimmune system,
which cells were invovled and how we can further enhance this process. We also discovered via theis grant
several new means to deliver gene scilencing in vivo. This work was published in several articles. Finally, the
work here has opened up an entriely new field of research that suggests that miRNAs, naturally occuring gene
scileincing genes within our own cells, are primarily invovled in regulating immune presentaion of our
proteins. This work has givien us an new understanding of this process and will allow us to design new
therapies that harness the body's immune system as well as fight the cancer directly.
Expected future outcomes:
From this work we plan a clincial trial in cerical cancer patients to test our new delivery and gene scilencing
therapies. The discoveries made here have also opened up an entirely new field of research in the area of
miRNAs, proposing their true function is to regulate self-presentaion of proteins.
Name of contact:
Nigel Mcmillan
Email/Phone no. of contact:
n.mcmillan@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1011955
CIA Name: Prof Jiri Neuzil
Admin Inst: Griffith University
Main RFCD: Cancer Cell Biology
Total funding: $448,435
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Mitochondrial complex II is a new target for anti-cancer drugsMitochondrial complex II is a new target for
anti-cancer drugs
Lay Description (from application):
Cancer is a huge problem and is most likely to get worse. Therefore, new approaches to treatment are
necessary. Cancer cells constantly mutate, so many established drugs cannot be used. A very promising
approach is targeting mitochondria, the powerhouse of the cells. This is because these organelles are important
for all cancer cells. We are proposing a novel way of using mitochondria as targets for a group of anti-cancer
drugs that would ultimately result in efficient cancer management.
Research achievements (from final report):
Cancer is a disease with high level of mortality therefore new treatments are needed. One potential and not yet
utilised target for cancer treatment are mitochondria organelles that provide energy for cancer cells. Therefore
it appears logical that hitting their mitochondria may harm cancer cells and that this could lead to novel anticancer strategies. In this project we focused on development and testing of new anti-cancer drugs based on
vitamin E that by specific chemical modification specifically targets mitochondria to selectively kill cancer
cells. We show that this approach makes anti-cancer drugs more efficient and keep their selectivity for tumour
cells causing only marginal harm to normal cells. We document that these agents represented by
mitochondrially targeted vitamin E succinate veruy efficiently suppress several types of tumours breast cancer
colorectal cancer and mesothelioma in mouse model.
Expected future outcomes:
We expect that this research will result in the future in translational studies that will eventually lead to the
design testing and possibly clinical use of novel anti-cancer drugs that suppress hard-to-treat tumours breast
cancer with high HER2 mesothelioma.
Name of contact:
Jiri Neuzil
Email/Phone no. of contact:
j.neuzil@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145702
CIA Name: Prof Patrick Sexton
Admin Inst: Howard Florey Institute
Main RFCD: Basic Pharmacology
Total funding: $392,037
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
G-protein receptor interactionG-protein receptor interaction
Lay Description (from application):
The maintenance of optimum health and function of living cells, and consequently that of the whole organism,
depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them.
The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by
directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a
receptor. In one class of such receptors called G protein coupled receptors, the transmission of the message to
the interior of the cell involves yet another protein called G protein. It is extremely important to unravel how
each of these components, the stimulating agent, the receptor and G protein, works in order to understand how
the cells respond to various chemical signals. To make this process even more complex, it was recently shown
that another newly discovered group of proteins called receptor activity modifying proteins (RAMPs) too play
a critical role in some systems. Understanding what actually is the role of these new players, and how they
team-up with the other components to elicit a specific response to a chemical stimulus, forms the basis of this
proposal. Such knowledge is central to the unraveling of the processes involved in the maintenance of health,
abnormalities that lead to disease, and in the development of new treatments.
Research achievements (from final report):
This work led to new understanding on the importance of accessory protein interaction with G protein coupled
receptors (the major sites of pharmaceutical drug interaction). Further work will include examining the
mechanisms that underlie RAMP-induced changes in signalling. This work is important for understanding how
this important class of receptors function.
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 145703
CIA Name: Prof Patrick Sexton
Admin Inst: Howard Florey Institute
Main RFCD: Basic Pharmacology
Total funding: $227,037
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Analysis of calcitonin - receptor interactionsAnalysis of calcitonin - receptor interactions
Lay Description (from application):
Receptors form a basic intermediary as the acceptor site for signals that are transmitted between the cells that
make up our body. Modulation of receptors, therefore, forms a key target in our ability to treat disease. The
largest class of receptors is the superfamily of G protein-coupled receptors (GPCRs), which transmit signals
within a cell via proteins called G proteins. GPCRs form between 1 and 5% of the entire repertoire of human
genes. One group of GPCRs provide the target for small protein molecules that circulate through the body. One
such circulating molecule is calcitonin, a peptide that plays an important role in maintaining circulating
calcium levels in the body, which is essential for proper maintenance of the skeleton. As a consequence of this
action, calcitonin is an important clinically used tool in the treatment of bone disease such as osteoporosis and
Paget's disease. Due to the molecular nature of calcitonin and its receptor (and other related receptors) that have
a broad, complex mechanism of interaction, we have very little definitive information on how calcitonin
interfaces with its receptor to signal to target cells. The current project utilises a novel method of permanently
linking calcitonin to its receptor, allowing identification of how the two components come together. This
information provides important fundamentals for understanding how this and related receptors work and the
potential for rational design of improved therapeutic tools.
Research achievements (from final report):
The work has provided advances in knowledge of how calcitonin peptides (which are used therapeutically to
treat bone diseases including osteoporosis and Paget’s disease) interact with their cognate receptors. This,
together with ongoing work, is contributing to dynamic models of how peptide hormones interact with
receptors (which is poorly understood due to lack of high resolution structural information). It has implications
for the mode of action of both calcitonin peptides, but also more broadly for the mode of action of other related
peptide hormone receptors.
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 150401
Start Year: 2001
CIA Name: A/Pr Andrew Zannettino
End Year: 2003
Admin Inst: Institute of Medical and Veterinary Science
Grant Type: NHMRC Project Grants
Main RFCD: Haematology
Total funding: $212,037
Title of research award:
The Molecular And Cellular Mechanisms Responsible For The Skeletal Complications Associated with
Multiple Myeloma.The Molecular And Cellular Mechanisms Responsible For The Skeletal Complications
Associated with Multiple Myeloma.
Lay Description (from application):
Multiple myeloma is an incurable disease of the antibody-producing B cell. Patients with MM, nearly always
present with bone pain and unexplained bone fractures. These fractures are caused by the cancerous MM B
cells, which are found in large numbers in discrete pockets throughout the bone marrow, close to the inner bone
surface. The way that the cancerous B cells cause the local bone lesions is thought to be through the heightened
activation of recruitment of osteoclasts. Osteoclasts are cells which normally, in a controlled manner, resorb
bone as part of the ongoing process of new bone formation. We propose that myeloma cells, which exhibit
characteristics of osteoclasts, home to sites in the bone marrow and initiate this bone breakdown and
furthermore secrete factors required for osteoclast maturation and activity. We believe that these molecules
include the recently defined molecule, termed osteoclast differentiation factor, which is normally produced by
bone-producing cells known as osteoblasts. Moreover, we feel that myeloma B cells alter the function of
osteoblast cells, which results in a decrease in bone formation. Finally, we propose that this disease and its
associated bone defects originate from changes in the expression of a number of genes. The results from theses
studies should provide a greater understanding of the way in which this B cell cancer originates and how it
causes bone defects. This will lead to the development of better treatments to improve the survival of patients
with MM, and will lead to therapies to prevent the associated bone complications.
Research achievements (from final report):
One of the most debilitating complications of the bone marrow cancer, multiple myeloma, is the skeletal
destruction which is caused by heightened production and activation of osteoclasts. Osteoclasts represent cells
which normally function in a controlled manner, to remove unwanted bone. Our recent studies show that
myeloma plasma cells express a potent osteoclast growth factor, termed RANKL, and are capable of directly
supporting osteoclast formation. In addition, RANKL expression by myeloma plasma cells appears to
positively correlate with the degree of skeletal destruction making it a potential prognostic marker of skeletal
involvement and a key therapeutic target. Our more recent studies have identified additional factors which, like
RANKL, also increase osteoclast activity. These findings may ultimately provide us with novel targets to
which drugs may be developed that could be used to reduce the morbidity associated with cancer-mediated
bone loss. Moreover, it may also provide us with therapies which may counter other bone-related diseases
including osteo-arthritis and osteoporosis.
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 150404
Start Year: 2001
CIA Name: Dr Joanna Woodcock
End Year: 2003
Admin Inst: Institute of Medical and Veterinary Science
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $212,037
Title of research award:
The regulation of 14-3-3 protein function by post-translational modificationThe regulation of 14-3-3 protein
function by post-translational modification
Lay Description (from application):
The cells of our body have control mechanisms that prevent them from growing abnormally. However, when
cells become cancerous they escape the normal checks and controls and are able to survive, divide and grow
uncontrollably. In the last decade the molecular basis of several of the control mechanisms involved in
preventing cancerous growth have been uncovered. However, our understanding is far from complete and
recent research reports suggest that we have thus far overlooked a whole level of regulation of cell growth
control. Signals that instruct a normal cell to divide are propogated by pathways of interacting molecules
within the cell. These pathways are regulated by switch mechanisms that either modify the interacting
molecules, thereby inactivating their activity or by controlling when and where the molecules are allowed to
interact. This spatial and temporal control mechanism is mediated by a family of specialised molecules, called
14-3-3 proteins. Recent research indicates that the function of these 14-3-3 proteins is also tightly controlled,
although as yet we don't understand how. This research proposal attempts to discover the molecular mechanism
of regulation of 14-3-3 function. An understanding of this process may provide new molecular targets for the
development of therapeutics against cancer.
Research achievements (from final report):
The grant funded basic research into a new area involved in cell function and regulation. As a result of the
award a new pathway has been identified that regulates cell survival and may be implicated in cancer
formation.
Expected future outcomes:
The discoveries arising from this grant may ultimately lead to the development of new drugs for the treatment
of cancer and/or heart disease. A provisional patent is currently held to this end.
Name of contact:
Joanna Woodcock
Email/Phone no. of contact:
joanna.woodcock@imvs.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 232905
Start Year: 2003
CIA Name: Dr Stuart Pitson
End Year: 2005
Admin Inst: Institute of Medical and Veterinary Science
Grant Type: NHMRC Project Grants
Main RFCD: Enzymes
Total funding: $442,500
Title of research award:
The molecular mechanism of sphingosine kinase activationThe molecular mechanism of sphingosine kinase
activation
Lay Description (from application):
Many cell processes like growth, death and differentiation are controlled by hormones and other molecules that
interact with receptors on the outside of the cell. When this type of molecule binds to a receptor, it often
triggers the production of signaling molecules inside the cell that initiate a change in the cells behaviour. The
lipid molecule, sphingosine phosphate has been identified as such a signaling molecule that appears to be
involved in the regulation of a diverse array of important mammalian cellular processes. Recent studies have
found that sphingosine phosphate is involved in the inflammation of cells, and if its production can be blocked,
inflammation is not seen. Therefore, this provides a potential target for therapeutic intervention in the
inflammation process. However, the manner by which cells regulate sphingosine phosphate levels is not well
known. It is known that sphingosine phosphate is produced by the enzyme sphingosine kinase, and strong
evidence suggests that changes in this enzyme's activity in the cell regulate sphingosine phosphate levels.
However, how the cell changes the levels of sphingosine kinase activity is completely unknown. This study
will investigate this problem with the view that understanding this process will allow the development of new
drugs to block increases in sphingosine kinase activity, preventing increases in sphingosine phosphate levels,
and it turn, preventing cellular inflammation.
Research achievements (from final report):
Sphingosine kinase is an enzyme that produces the lipid signalling molecule, sphingosine phosphate that is
involved in the regulation of a diverse array of important mammalian cell functions like growth, death and
differentiation. Sphingosine kinase is involved in tumorigenesis, and if its activity can be blocked, tumor size
can be reduced. Therefore, this provides a potential target for therapeutic intervention in cancer. However, the
manner by which cells regulate sphingosine kinase is not well known. In this study we have established that
phosphorylation of sphingosine kinase increases the activity of this enzyme, and also causes a shift in its
localisation within the cell. Importantly, we have also found that both of these processes are essential for the
tumorigenic effects of sphingosine kinase. Thus, this study has identifed potential therapeutic targets that can
be exploited for the development of new drugs to block the tumorigenic effects of sphingosine kinase.
Expected future outcomes:
The findings of this study are likely to provide the basis for the search for new anti-cancer therapies targeting
the regulation of sphingosine kinase.
Name of contact:
Stuart Pitson
Email/Phone no. of contact:
stuart.pitson@imvs.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 278802
Start Year: 2004
CIA Name: Dr Yeesim Khew-Goodall
End Year: 2006
Admin Inst: Institute of Medical and Veterinary Science
Grant Type: NHMRC Project Grants
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $496,500
Title of research award:
A tyrosine phosphatase that regulates adherens junctions, cell migration and the epithelial-mesenchymal
transitionA tyrosine phosphatase that regulates adherens junctions, cell migration and the epithelialmesenchymal transition
Lay Description (from application):
Cell-cell adhesion which physically glues cells together to form tissues and organs, also controls processes in
development, wound healing and cancer progression. I have identified a novel regulator of cell-cell adhesion
that regulates cell migration and cell morphology. Since these events are crucial during metastasis (the spread
of cancer) and during wound healing, understanding the function of this novel regulator may provide the basis
for new approaches to developing therapeutics. Specifically, in this proposal I aim to further our understanding
of the function of this novel regulator in normal physiology and to elucidate how its functions are regulated.
Research achievements (from final report):
In this study, we (i) demonstrated that the protein tyrosine phosphatase Pez is a regulator of epithelialmesenchymal transition (EMT), (ii) that its role in regulating EMT is crucial for the proper development of
some organs using a zebrafish model to study organ development and (iii) that it is a regulator of the growth
factor TGF-beta production leading to the EMT. In addition to its role in organ development, EMT is also a
process required for the initial stages of metastasis of solid tumours as well as a source of additional fibroblasts
in fibrotic diseases that lead to organ failure. Although TGF-beta level is well-known to be elevated in both
cancers and fibrotic diseases and play a role in the progression of both these diseases, little is known about the
mechanisms that lead to elevated TGF-beta levels in these diseases. Our findings implicate Pez as a potential
protagonist of both cancer metastasis and organ fibrosis and hence a potential therapuetic target for novel drugs
to inhibit or retard these processes. The findings from this study and reagents generated as a result led to a
collaboration with a colleague in which we identified a family microRNAs that could regulate EMT with
implications for their use in preventing or retarding metastasis.
Expected future outcomes:
We expect that in future we will establish a role for Pez in metastasis and fibrotic diseases and head towards
determining whether it is a worthy therapeutic target for controlling cancer progression and/or fibrotic diseases.
We will also establish the mechanism by which Pez upregulates active TGF-beta and this would impact on our
undestanding of developmental processes, homeostasis and diseases.
Name of contact:
Yeesim Khew-Goodall
Email/Phone no. of contact:
yeesim.khew-goodall@imvs.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 328606
Start Year: 2005
CIA Name: Dr Philip Gregory
End Year: 2008
Admin Inst: Institute of Medical and Veterinary Science
Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Gene Expression
Total funding: $271,500
Title of research award:
MicroRNA regulation of genes involved in angiogenesisMicroRNA regulation of genes involved in
angiogenesis
Lay Description (from application):
Not Available
Research achievements (from final report):
As a result of funding through a Peter Doherty Training Fellowship I was able to discover a group of
microRNAs (the miR-200 family and miR-205) and demonstrate they are key regulators of epithelialmesenchymal transition (EMT). EMT is a process that occurs during normal embryonic development to allow
epithelial-derived cells to lose their epithelial features and acquire mesenchymal characteristics, endowing
them with the ability to migrate and differentiate into the precursors of new tissues. EMT is also currently one
of the most intensely studied areas in cancer research, with strong evidence indicating it plays a important role
in the metastasis of epithelial tumours. As epithelial carcinomas (such as breast, lung, prostate, and colon)
account for more than 80% of cancers in humans and the vast majority of deaths are due to tumour metastasis
these finding have great therapeutic interest and potential. I found that the miR-200 family are lost in
mesenchymal breast cancers that are invasive suggesting these microRNAs may be important for breast cancer
metastasis. These findings have received international acclaim and were published in Nature Cell Biology,
Cancer Research and a number of review articles which have had a major impact on the field of EMT and
metastasis research.
Expected future outcomes:
This discovery has great potential in providing a novel treatment to inhibit the metastasis of epithelial cancers
such as breast, lung, prostate, and colon
Name of contact:
Dr. Philip Gregory
Email/Phone no. of contact:
philip.gregory@imvs.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 379000
Start Year: 2006
CIA Name: Dr Joanna Woodcock
End Year: 2008
Admin Inst: Institute of Medical and Veterinary Science
Grant Type: NHMRC Project Grants
Main RFCD: Pathology
Total funding: $524,771
Title of research award:
Regulation of 14-3-3 monomerisation controls cell life/death fateRegulation of 14-3-3 monomerisation controls
cell life/death fate
Lay Description (from application):
14-3-3 proteins are becoming increasingly recognised as major multifunctional proteins that control key
aspects of normal and pathological processes. Although initially viewed as inert components of signalling, we
have now recognised for the first time that these are very dynamic proteins that can be regulated. Our main aim
is to understand the regulatory mechanisms controlling the different dynamic forms of 14-3-3 and how each
form in turn controls the process of life and death.
Research achievements (from final report):
We have discovered an important process which controls the life/death fate of normal cells. Our studies show
that cancer cells escape this control by acquiring new traits.
Expected future outcomes:
This research will lead to the development of new anti-cancer treatments in the future.
Name of contact:
Dr Joanna Woodcock
Email/Phone no. of contact:
joanna.woodcock@imvs.sa.gov.au
NHMRC Research Achievements - SUMMARY
Grant ID: 443044
CIA Name: Dr Jason Mulvenna
Admin Inst: James Cook University
Main RFCD: Medical Parasitology
Total funding: $282,008
Start Year: 2007
End Year: 2010
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Characterisation of secreted immunoregulatory proteins from parasitic helminthsCharacterisation of secreted
immunoregulatory proteins from parasitic helminths
Lay Description (from application):
Not Available
Research achievements (from final report):
During the course of this training fellowship, advanced techniques were used for the characterisation of
proteins important in the establishment and maintenance of human parasite infection. Using proteomic, laser
microdissection and bioinformatics techniques potential vaccine and drug targets were identified for some of
the most important helminth parasites of humans, including hookworms and blood and liver flukes. This work
was directly responsible for the identification of vaccine targets for hookworm that are currently undergoing
clinical trials and for the generation of leads for the development of new drugs to target Schistosoma mansoni
and Opisthorchis viverrini. In addition to this, work conducted during the course of this fellowship resulted in
the identification of a mitogenic protein from the cancer causing parasite, O. viverrini, which is now the subject
of ongoing research into the basic mechanisms of carcinogenesis and the complex relationship between
inflammation and carcinogenesis. The advanced mass spectroscopy techniques developed during this
fellowship are now being exploited for the identification of diagnostic biomarkers for intractable and hard to
detect cancers, such as cancer of the liver and pancreas. This work has the potential to revolutionise cancer
treatment and provide many extra years of life for sufferers of these pernicious diseases by both identifying
those at risk for developing the cancers and by providing the means for the early detection and timely treatment
of cancers that are undetectable until it is too late.
Expected future outcomes:
The results acheived during this fellowship will provide future drug and vaccine targets for parasitic diseases,
provide a better understanding of the relationship between inflammation and cancer and provide better
diagnostics for the timely detection of a number of different cancers.
Name of contact:
Jason Mulvenna
Email/Phone no. of contact:
jason.mulvenna@qimr.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 613669
CIA Name: Prof Alexander Loukas
Admin Inst: James Cook University
Main RFCD: Medical Parasitology
Total funding: $489,123
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Interactions between excretory-secretory proteins of the carcinogenic liver fluke and host cellsInteractions
between excretory-secretory proteins of the carcinogenic liver fluke and host cells
Lay Description (from application):
Throughout East Asia, there is a strikingly high prevalence of cholangiocarcinoma (CCA - cancer of the bile
ducts) in regions where the human liver fluke is endemic. How the parasite casues cancer is multi-factorial, but
one suspected mechanism is via the secretion of parasite proteins that enter bile duct cells and cause them to
proliferate. We aim to understand this process and ultimately develop new control strategies to reduce the
prevalence or the infection and CCA.
Research achievements (from final report):
The oriental liver fluke infects millions of people throughout SE Asia where it is a major cause of bile duct
cancer. The mechanisms by which the fluke causes are cancer are multfactorial and include the secretion of
proteins from the fluke that drive proliferation of bile duct epithelial cells and establish an environment that
predisposes to cancer development. We identified the mechanism by which liver fluke secreted proteins enter
host biliary cells and drive changes in gene and protein expression within those cells. The parasite secretes
exosomes, small vesicles that originate from other cells (such as the outer membrane of the fluke), that are
taken up by host biliary cells and can be detected inside those cells using proteomics and fluorescence
microscopy approaches. Uptake of parasite exosomes drives changes in the biliary cell including upregulation
of proteins associated with cell proliferation and cancer development, and down regulation of molecules such
as tumor suppressor proteins.
Expected future outcomes:
This work helps to explain why parasitic liver flukes are considered a group 1 carcinogen and wil laid in the
development of new therpaeutics to control this infection.
Name of contact:
Paul Brindley
Email/Phone no. of contact:
pbrindley@gwu.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 234418
CIA Name: Prof Judith Lumley
Admin Inst: La Trobe University
Main RFCD: Epidemiology
Total funding: $98,600
Start Year: 2003
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Perinatal outcomes following treatment for cervical dysplasiaPerinatal outcomes following treatment for
cervical dysplasia
Lay Description (from application):
A very high proportion of women in Australia have regular cervical screening ('pap' tests) for early detection of
any early abnormal changes of the cervix. Women with abnormalities are referred for further investigation and
some go on to have the areas with abnormalities treated either by surgical removal of small amounts of tissue
or by other heat or laser treatments of affected areas. Many women having these treatments are of child-bearing
age and may not have had children, or may seek to have more children after treatment. There are unanswered
questions about the extent to which any or all of these treatments might, by changes to the cervix, lead to
preterm birth in any subsequent pregnancy. In the proposed study, records relating to women referred from
1982 to 2000 for assessment and possible treatment of cervical abnormalities at a major hospital will be linked
to Victorian birth records from 1983 to 2001. This will allow a comparison of preterm birth in the group of
women referred with cervical abnormalities, with preterm births in the Victorian population, and comparing
women who do and don't have treatment, taking into account other important factors such as the mother's age,
and her previous pregnancies. The information will be of value to women themselves, to gynaecologists and to
screening services.
Research achievements (from final report):
The study found that both women who were assessed but did not go on to have treatment and women who had
treatment for pre-cancerous changes in the cervix were at an increased risk of giving birth preterm. In addition,
the study found that excisional, but not ablative treatment appeared to convey an additional risk. The findings
of the study add weight to the growing body of evidence that suggest that excisional treatments may be
associated with an increased risk of preterm birth. This information can be provided to clinicians and women
when considering treatment options, particularly if the woman is of child-bearing age and will assist informed
decision-making. The findings from the study were published in the British Journal of Obstetrics and
Gynaecology.
Expected future outcomes:
Follow-up research is currently underway examining the relationship between the size of the excision and
pregnancy outcomes. A proposal is being developed for a prospective study
Name of contact:
Fiona Bruinsma
Email/Phone no. of contact:
f.bruinsma@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 237147
Start Year: 2003
CIA Name: Dr Christine Hawkins
End Year: 2008
Admin Inst: La Trobe University
Grant Type: Career Development Fellowships
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $435,500
Title of research award:
Isolation and analysis of novel apoptic pathway componentsIsolation and analysis of novel apoptic pathway
components
Lay Description (from application):
Not Available
Research achievements (from final report):
Tight regulation of the balance between cellular survival and death is vital for good health, and dysregulation
contributes to many diseases including cancer and autoimmune diseases. The research funded by this award
clarified the roles of a number of cell death regulators and identified other potential regulators. A major aspect
of this work focussed on the evolutionary conservation of cell death pathways. A number of projects probed the
cell death pathway of the nematode worm C. elegans. We defined the substrate specificity of the sole apoptotic
caspase of nematodes, CED-3. We also evaluated the ability of mammalian cell death regulators to substitute
for their apparent counterparts in nematodes, demonstrating that the human oncogene Bcl-2 works via a
different mechanism of action to its closest nematode relative, CED-9. In a separate study we characterised the
activity of p49, the second member of the p35 family of insect virus apoptosis inhibitors. Other projects
investigated the potential of novel anti-cancer agents to target brain tumour cells. Disappointingly, our results
predict that a minority of patients diagnosed with malignant glioma would respond to TRAIL, a previously
promising experimental agent. However, in vitro techniques developed during this project may help predict the
responses of tumours from patients to various anti-cancer agents, thus helping oncologists tailor therapies for
individual patients.
Expected future outcomes:
Current projects include an in vitro assessment of the anti-glioma potential of a new drug. If our assays
demonstrate selectivity for tumour cells relative to normal cells, this information will contribute to the
development of this agent as a new therapy for glioma patients. Novel cellular and viral apoptotic regulators
that we identify may be targets for anti-viral or anti-cancer agents.
Name of contact:
Christine Hawkins
Email/Phone no. of contact:
c.hawkins@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284513
Start Year: 2004
CIA Name: Dr Christine Hawkins
End Year: 2006
Admin Inst: La Trobe University
Grant Type: NHMRC Project Grants
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $253,500
Title of research award:
Dissection of the mechanisms of action of evolutionarily conserved apoptotic pathway componentsDissection
of the mechanisms of action of evolutionarily conserved apoptotic pathway components
Lay Description (from application):
Animals eliminate unwanted cells through a highly controlled process termed apoptosis. Defects in apoptosis
can contribute to cancer or autoimmune disease. Conversely, diseases such as stroke and Alzheimer's disease
have been linked to excessive cell death. To develop drugs that promote apoptosis when it fails to occur, or
prevent inappropriate cell death, it is necessary to elucidate the molecular mechanisms controlling apoptosis.
The first recognised component of the mammalian cell death machinery was Bcl-2; a protein associated with
development of cancer. Despite much research since then, the way in which Bcl-2 and related proteins function
is still unknown. This project capitalises on previous genetic and biochemical studies in a model genetic
organism (the roundworm) to address this important issue. Animal cell death pathway components can be
introduced into yeast such that activation of the introduced pathways leads to yeast death and its inhibition
promotes yeast survival. We have used this approach to reconstitute the worm cell death pathway and a major
mammalian apoptosis pathway in yeast. Yeast strains bearing these reconstituted pathways will be used to test
functional equivalence of candidate mammalian proteins and their putative roundworm counterparts. The
system will also be exploited to identify and characterise novel proteins that regulate cell death in mammals
and worms. Understanding the way in which key molecules regulate apoptosis will assist in the development of
diagnostic and therapeutic reagents for many diseases in which cell death regulation is perturbed. This project
capitalises on the evolutionary conservation of apoptosis to characterise the mechanisms of action of important
mammalian apoptotic regulators and to seek novel mammalian apoptotic pathway components. Proteins
identified in this way are likely to be important apoptotic regulators, as our approach ensures that their
functions are evolutionarily conserved.
Research achievements (from final report):
In this project we explored the evolutionary conservation of important apoptotic pathways. We reconstituted
the nematode (CED-3, CED-4, CED-9, EGL-1) and mammalian apoptosome (caspase-3, caspase-9, Apaf-1)
pathways using a yeast-based system. These systems capitalised on the ability of active caspases to kill yeast,
via a mechanism that we found involved disruption of the plasma and nuclear membranes, but did not involve
DNA damage. We exploited the reconstituted nematode pathway to define the mechanism of action of CED-9.
Our data confirmed the ability of CED-9 to inhibit CED-4, but refuted a previous report suggesting that CED-9
may also directly affect CED-3 activity. Using these models we also tested the abilities of candidate
mammalian homologues to functionally replace their counterparts from nematodes, and vice versa. In
particular we focussed on the mechanism of action of Bcl-2, a mammalian apoptosis inhibitor that can inhibit
nematode cell death. Importantly, we demonstrated that, contrary to a widely held assumption, Bcl-2 could not
directly inhibit CED-4. Other mammalian Bcl-2 relatives tested were also unable to substitute for CED-9 to
inhibit CED-4. Our results instead suggested that the ability of Bcl-2 to inhibit programmed cell death in
nematodes reflects its ability to prevent EGL-1-mediated sequestration of CED-9. These findings constitute
important contributions to our understanding of the mechanisms by which cell death is controlled in
evolutionarily divergent organisms.
Expected future outcomes:
Our findings highlight differences in the mechanisms of action of CED-9 and Bcl-2. They raise the possibility
that as-yet unidentified mammalian proteins may play roles analogous to that played by CED-9 in worms (ie
inhibition of caspase activators). Ongoing studies are exploring this possibility.
Name of contact:
NHMRC Research Achievements - SUMMARY
Christine Hawkins
Email/Phone no. of contact:
c.hawkins@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 356256
Start Year: 2005
CIA Name: Dr John Silke
End Year: 2008
Admin Inst: La Trobe University
Grant Type: Career Development Fellowships
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $381,500
Title of research award:
Homeostatic regulation of IAP RING finger proteins and its relevance to tumour therapyHomeostatic
regulation of IAP RING finger proteins and its relevance to tumour therapy
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
This RD Wright career development grant was awarded from January 1st 2005.The clearest proof that this
development grant was successful is demonstrated by the fact that I obtained an NHMRC Senior Research
Fellow A fellowship a year before my RD Wright development grant was due to expire. My work resulted in
discoveries about the mechanism of a novel anti-cancer drug that were publishedin the Cell and Journal of
Biochemistry and which have led to the fast tracking of the drug into human clinical trials
Expected future outcomes:
I will hold the SRFA for the following 5 years
Name of contact:
John Silke
Email/Phone no. of contact:
J.silke@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 380852
Start Year: 2006
CIA Name: Prof Don Phillips
End Year: 2006
Admin Inst: La Trobe University
Grant Type: NHMRC Development Grants
Main RFCD: Therapies and Therapeutic Technology
Total funding: $208,350
Title of research award:
Proof of principle of the activation of anthracycline anticancer agents by formaldehyde-releasing prodrugs in
mouse xenoProof of principle of the activation of anthracycline anticancer agents by formaldehyde-releasing
prodrugs in mouse xeno
Lay Description (from application):
Not Available
Research achievements (from final report):
We used a mouse model where mice were implanted with human breast tumours in order to test the feasibility
of a new anticancer drug treatment strategy. In this mouse model study we demonstrated that if the clinically
used anticancer drug doxorubicin is delivered systemically (intravenously) and the activating agent
(formaldehyde) is delivered by intra-tumoural injection of the formaldehyde-releasing prodrug, then this
greatly enhances the inhibition of the tumour compared to treatment by either compound as a single agent. The
prodrug that released two molecules of formaldehyde (AN-193) was also more effective than AN-9 (that
released one molecule of formaldehyde), also consistent with the hypothesis that anthracycline agents such as
doxorubicin can be activated by formaldehyde to yield enhanced anticancer activity. , , The significance of this
postive outcome is that it demonstrates that the widely used anticancer anthracyclines such as doxorubicin can
have their activity enhanced, thereby offering the prospects of obtaining enhanced tumour responses, or of
using lower doses in the clinic in order to achieve reduced side-effects. A third benefit is that it now provides a
mechanism to achieve tumour-localised chemotherapy with anthracyclines by localising the activating agent (a
formaldehyde-releasing prodrug) to tumours, and this is feasible because of the relatively simple chemistry of
the prodrugs.
Expected future outcomes:
The positive outcome to this proof-of-principle study now justifies the development of tumour-localised release
of formaldehyde and these will now be evaluated in order to develop tumour-localised chemotherapy.
Name of contact:
Professor Don Phillips
Email/Phone no. of contact:
d.phillips@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 471424
Start Year: 2008
CIA Name: Dr Mark Hulett
End Year: 2011
Admin Inst: La Trobe University
Grant Type: NHMRC Project Grants
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $580,849
Title of research award:
Dissecting the function of heparanase in inflammatory disease using genetic tissue-specific ablationDissecting
the function of heparanase in inflammatory disease using genetic tissue-specific ablation
Lay Description (from application):
This project aims to define the role of the enzyme heparanase in a number of important diseases, namely
Inflammatory/autoimmune diseases such as multiple scelorosis and rheumatiod arthritis, and the growth and
spread of cancer. Heparanase has been implicated for many years in promoting these diseases however its
precise contribution has not beed defined. These studies will provide definitive information whether
heparanase is a valid therapuetic target in these important disease settings.
Research achievements (from final report):
The aims this project were to define the role of the heparan sulphate degrading enzyme heparanase in
inflammatory disease using constitutive gene knockout mice. Heparanase KO mice were generated and
characterised in the context of: (i) the vascular compartment, (ii) the role of heparanase in leukocyte migration
using inflammatory models, and (iii) establishing the Rip1-tag2 tumour progression model in the heparanse KO
mice. Characterisation of the blood vascular of the heparanase knockout mice indicated that the mice showed
no significant differences to wild-type mice. Detailed analysis of the role of heparanase in leukocyte migration
was investigated using 3 models (i) DC migration using an antigen-skin paint model, (ii) a DC-dependent
mouse dust mite airways hypersensitivity model, and (iii) actively induced EAE model. In each of the 3 models
there was evidence of reduced leukocyte migration with (i) significantly lower numbers of dermal DC and
Langerhan's cell migration from the skin to the local lymph node, (ii) reduced infiltration of airways with
migrating DC and other leukocytes e.g. eosinophils resulting a significant reduction in the Th2-mediated
inflammatory response, and (iii) reduced T cell infiltrate in the CNS of mice with EAE, respectively. These
data provide direct evidence that heparanase plays an important role in promoting leukocyte migration during
inflammation and thus identifies the enzyme as a potential target for the treatment of inflammatory disease.
Expected future outcomes:
This research lays the platform for ongoing detailed studies into the role of heparanase as a key contributor to
inflammation and investigation of the potential of the enzyme as a drug target for the treatment of
inflammatory disease.
Name of contact:
Dr Mark D Hulett
Email/Phone no. of contact:
m.hulett@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 487311
Start Year: 2008
CIA Name: Dr Hamsa Puthalakath
End Year: 2011
Admin Inst: La Trobe University
Grant Type: NHMRC Project Grants
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $558,189
Title of research award:
DETERMINING THE ROLE OF ER STRESS INDUCED APOPTOSIS IN THYMIC NEGATIVE
SELECTIONDETERMINING THE ROLE OF ER STRESS INDUCED APOPTOSIS IN THYMIC
NEGATIVE SELECTION
Lay Description (from application):
Apoptosis is an evolutionarily conserved mechanism for killing unwanted cells that are no longer needed,
damaged, infected with pathogens or dangerous. Defects in apoptosis can cause a number of diseases. For
example, abnormal survival of cells can cause cancer or autoimmune disease. Bim is a protein that induces
apoptosis and act as a barrier against cancer and autoimmune diseases. This work is aimed at understanding
how Bim acts as a barrier against the development of autoimmunity.
Research achievements (from final report):
This project was aimed at understanding the role of ER stress in thymic negative selection. Understanding the
molecular mechanism of this process would have profound implications for the wider understanding of how
auto-immunity develops. However, soon after the project started, our results clearly showed that ER stress did
not have any role in determining the outcome of thymic selection. Instead, we found that it was the
transcription factor c-Myc that regulated the cell death process during thymic selection. Subsequently, our
effort was focused towards understanding the molecular mechanism of c-Myc induced apoptosis. Our results
clearly demonstrate that c-Myc together with the co-factor CBP regulates the apoptosis process by inducing
epigenetic modifications at the bim locus which, in turn, regulates the apoptosis mechanism. To better
understand this in an in vivo system, we generated a knock-in mouse model where c-Myc biding sites on the
bim promoter are mutated. Analysis of the cells from these mouse showed that bim expression was muted in
these cells and they don't respond to stress hormones such as beta-adrenergic catecholamines. These findings
have implications for understanding the molecular basis of the stress-induced diseases in humans i.e.
cardiomyopathy and immune deficiency. Furthermore, we are in the process of designing a high throughput
screening strategy for developing drugs that can counter the apoptosis process.
Expected future outcomes:
Through this project, though we did not achieve the initial objective, we have been able to understand the
molecular basis of two major human diseases i.e. cardiomyopathy and immune deficiency. We are in the
process of validating our findings in in vivo models and developing therapeutic drugs against these.
Name of contact:
Hamsa Puthalakath
Email/Phone no. of contact:
h.puthalakath@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 487333
Start Year: 2008
CIA Name: Dr Suzanne Cutts
End Year: 2010
Admin Inst: La Trobe University
Grant Type: NHMRC Project Grants
Main RFCD: Medical Biochemistry: Nucleic Acids
Total funding: $471,703
Title of research award:
Rational design and development of new anthracenedione derivativesRational design and development of new
anthracenedione derivatives
Lay Description (from application):
Our laboratory has discovered a way to activate the anti-cancer drug mitoxantrone to make it bind to DNA
more effectively. This involves pre-activating it with the simple molecule formaldehyde. This concept has
enabled us to design new anticancer drugs that are predicted to be more effective at killing cancer cells. In this
study we will synthesise these new compounds then test how effectively they bind to DNA, inhibit growth of
tumour cells in culture, and inhibit growth of tumours in mice.
Research achievements (from final report):
In this study we designed and synthesised new anticancer drugs based on the structure of the clinically used
anticancer drug mitoxantrone. We were successful in improving upon several characteristics of the parent
compound. Firstly, we synthesised a compound that is better at targeting the enzyme topisomerase II (the target
via which mitoxantrone kills cancer cells), more potently induces DNA damage, and kills several types of
tumour cell to a greater degree than the parent compound mitoxantrone. Secondly, we synthesised a compound
that, unlike mitoxantrone, binds covalently to DNA when activated by formaldehyde. This compound is nontoxic as a single agent but upon activation potently kills cancer cells. Further development of these compounds
(eg. to enhance their accumulation in the cell nucleus to enhance DNA accessibility) may yield new
compounds that can ultimately be utilised in the clinic. In addition, a new high throughput screening assay was
optimised as a new tool to rapidly assess the ability of new compounds to bind stably to DNA. This new tool
may have applications not only in identifying potential anticancer agents, but also agents that are potential
mutagens and carcinogens.
Expected future outcomes:
Further drug synthesis based on our lead compounds, or packaging in nanoparticle formulations for targeted
tumour delivery, is expected to improve the therapeutic profile of these new anthracenedione compounds.
Name of contact:
Suzanne Cutts
Email/Phone no. of contact:
s.cutts@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 487348
CIA Name: Dr Ian Gentle
Admin Inst: La Trobe University
Main RFCD: Cell Metabolism
Total funding: $195,381
Start Year: 2008
End Year: 2010
Grant Type: Early Career Fellowships (Australia)
Title of research award:
A metabolomic analysis of programmed cell death.A metabolomic analysis of programmed cell death.
Lay Description (from application):
Apoptosis is a fundamental mechanism in regulating normal development and preventing cancer. Cancer cells
must avoid apoptosis and also adapt to harsh metabolic environments in order to survive in the absence of
effective nutrient supply and to resist the action of certain drugs. This project will provide a detailed analysis of
metabolic changes allowing cells to survive long periods when the apoptotic process is absent and nutrients are
limiting.
Research achievements (from final report):
This work has resutled in some improvement in the methods of analysis for metabalomic data which will be
useful in further research into metabolic studies. In addition the work has highlighted new and significant roles
for proteins regulating signalling from TNF receptors. This has broad implications for inflammatory signalling
and regulation of cell death, processes important in a number of diseases.
Expected future outcomes:
further understanding of TNF signalling and the regulation of cell death by inflammatory cytokines such as
TNF.
Name of contact:
Ian Gentle
Email/Phone no. of contact:
ian.gentle@uniklinik-freiburg.de
NHMRC Research Achievements - SUMMARY
Grant ID: 508912
CIA Name: Dr Peter Lock
Admin Inst: La Trobe University
Main RFCD: Oncology and Carcinogenesis
Total funding: $560,435
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Role of a novel Tks5-Nck signaling pathway in cancer invasionRole of a novel Tks5-Nck signaling pathway in
cancer invasion
Lay Description (from application):
Invasion and metastasis are major causes of death in cancer patients. Our research has uncovered a "pathway"
that increases the invasive potential of tumour cells in vitro. We now aim to determine if the pathway is
relevant in invasion and metastasis in clinically relevant models; how a "drug" targeting the pathway affects
invasion and; the extent to which the pathway is active in human tumours. These studies may identify a new
molecular target for anti-invasive drugs.
Research achievements (from final report):
The main achievement of this research project was the discovery of a new mechanism involved in cancer cell
invasion and metastasis. We found that structures on cancer cells known as "invadopodia", which faciliate the
penetration of malignant cancer cells through tissues, is dependent on a molecular "invasion complex"
comprising of key proteins which interact in a highly defined manner. The development of anti-invasive
compounds which specifically target the invasion complex that we have uncovered could potentially be used to
treat cancer patients and to attenuate the spread of early-stage tumours. Such drugs could also be beneficial as
combination therapies with existing cytotoxic cancer drugs where the migration of a subset of tumour cells is
thought to enable cells to evade drug toxicity.
Expected future outcomes:
An expected future outcome of this research will be the testing and validation of antagonistic molecules
(designed to disrupt the invasion complex we have defined) to abolish invasion of cells in vitro and in pre
clinical models of invasion and metastasis.
Name of contact:
Peter Lock
Email/Phone no. of contact:
P.Lock@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 541930
CIA Name: Dr Christine Hawkins
Admin Inst: La Trobe University
Main RFCD: Oncology and Carcinogenesis
Total funding: $130,808
Start Year: 2009
End Year: 2010
Grant Type: Career Development Fellowships
Title of research award:
Analysis of apoptotic pathways to develop better therapies for unresponsive cancers.Analysis of apoptotic
pathways to develop better therapies for unresponsive cancers.
Lay Description (from application):
Tight control of the balance between cellular survival and death is important for normal development and to
avoid numerous diseases. Inappropriate survival of precancerous cells can contribute to oncogenesis. Anticancer therapies act by inducing a cellular self-destruct program in tumour cells, and blocks in pathways
controlling this process can lead to resistance to anti-cancer treatments. Defining cell death pathways will
enable the development of better therapies for incurable cancers.
Research achievements (from final report):
During this fellowship, my group investigated the ability of TRAIL to kill malignant glioma cells in vitro,
alone and in combination with a range of other agents. We found that TRAIL cooperates with IAP antagonists
to kill cells from many gliomas (manuscript submitted April 2012), suggesting that therapies employing this
combination of novel apoptosis-inducing agents may be useful for glioma patients. Surprisingly, we also
observed that TRAIL exhibited a mutagenic activity, potently provoking DNA damage in surviving cells
(Lovric and Hawkins, 2010). We examined the molecular mechanism underlying this activity. Our data predict
that unfortunately TRAIL may be not offer an advantage over traditional chemotherapy drugs in terms of the
risk to cancer survivors of developing subsequent therapy-related tumours. Another major project pursued
during this time focused on viral inhibitors of host apoptosis. We characterised the mechanism of action and
specificity of MaviP35, a new member of the P35 family of baculoviral anti-apoptotic proteins (Brand et al,
2011). Ongoing projects are characterising other viral apoptosis inhibitors.
Expected future outcomes:
Our investigations into the mutagenic capacities of direct apoptosis inducing drugs will help predict their likely
side effects. We expect our ongoing focus on viral apoptosis inhibitors to yield a large amount of novel data.
We have identified candidate novel viral inhibitors and are defining their host targets, and continue to probe the
mechanisms of action of previously identified inhibitors.
Name of contact:
Dr Christine Hawkins
Email/Phone no. of contact:
c.hawkins@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566553
CIA Name: Dr Belinda Parker
Admin Inst: La Trobe University
Main RFCD: Oncology and Carcinogenesis
Total funding: $442,573
Start Year: 2009
End Year: 2014
Grant Type: Career Development Fellowships
Title of research award:
Characterisation and therapeutic targeting of molecular pathways that promote breast cancer metastasis to
boneCharacterisation and therapeutic targeting of molecular pathways that promote breast cancer metastasis to
bone
Lay Description (from application):
Breast cancer that has spread to bone cannot be cured. Using the most clinically relevant model of breast
cancer available we have identified that tumour cells growing in bone need to suppress immune elimination (by
suppressing the Type I interferons) and invade through the bone tissue (by activation of cysteine cathepsins).
Studying the functional role of these pathways will provide novel insight into the mechanisms of breast cancer
spread to bone that can be augmented therapeutically.
Research achievements (from final report):
Breast cancer is a major problem for society, with 1 in 8 women likely to develop the disease in their lifetime.
Although the majority of breast cancer patients will not die of the disease, 15 % will develop cancer spread to
distant tissues. It is this spread, commonly to lung, bone, liver and/or brain that is associated with disease
mortality. Therefore, knowledge of how cancer spread occurs and how to target this therapeutically is critically
important. A major accomplishment during this fellowship was the discovery of an immune pathway that is
critical in blocking the spread of breast cancer to bone. We found that cancer cells hide from the immune
system by blocking key immune signals and that this event enabled their survival and growth in bone.
Importantly, switching this pathway back on therapeutically dramatically decreased breast cancer spread,
suggesting that such approaches may be beneficial for breast cancer patients. We also identified a cancer gene
signature that could predict patients more likely to have spread to bone and those that may benefit from
immune-based therapies. Even more importantly, this gene signature also predicts those patients that are not
likely to benefit, decreased the need for over treatment of patients that are not likely to develop cancer spread.
Expected future outcomes:
We are currently testing new methods for predicting cancer spread in large cohorts based on our findings. We
are also trialling new ways to stimulate these immune pathways and testing their activity in combination with
chemotherapy to find the best therapeutic setting for future pre-clinical testing.
Name of contact:
Belinda Parker
Email/Phone no. of contact:
Belinda.Parker@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 637336
Start Year: 2010
CIA Name: Dr Marc Kvansakul
End Year: 2012
Admin Inst: La Trobe University
Grant Type: NHMRC Project Grants
Main RFCD: Cancer Therapy (excl. Chemotherapy and Radiation Therapy)
Total funding: $311,867
Title of research award:
Targeting viral Bcl-2 proteins for therapyTargeting viral Bcl-2 proteins for therapy
Lay Description (from application):
Failure to correctly regulate cell death leads to a number of diseases, including cancers and auto-immune
diseases. Viruses have the ability to hijack the host cell death machinery for their own benefit. Viral infections
have been linked to a number of cancers. We aim to target the ability of viruses to hijack the process of cell
death to develop new treatments against virus-linked cancers including Burkitt's Lymphoma and
Nasopharyngeal Carcinoma.
Research achievements (from final report):
Our aim was to investigate if certain Burkitt lymphomas can be treated by targeting proteins from the virus that
is the root cause for the lymphoma development, the Epstein-Barr virus (EBV). We specifically investigated a
viral protein that confers strong protection against signals that trigger programmed cell suicide, an important
cellular mechanism that allows healthy development of tissues and organs. EBV subverts this process to
establish a chronic infection, and this can lead to the development of Burkitt lymphoma. We showed that the
protein BHRF1 from EBV can lead to resistance against chemotherapeutic drugs by developing a mouse model
of the disease that features BHRF1, and may be a potential target for treating Burkitt lymphomas. We then
discovered a lead molecule that is able to bind BHRF1 with high selectivity, and crucially spares cellular
proteins, and showed that it blocks the binding cleft of BHRF1 that allowst this protein to subvert cellular
suicide programs. We were able to show this using a crystal structure of BHRF1 bound with our lead molecule,
which now also serves as the starting point for a rational drug design effort to develop a potent BHRF1
antagonist. We ultimately hope that we can test this molecule in our Burkitt lymphoma mouse model to
evaluate how effective it is, and improve it to the point where we have a drug in hand that exclusively targets
the viral protein BHRF1 over any cellular proteins to yield therapeutics with minimal side effects.
Expected future outcomes:
We hope to further develop the lead molecule into an effective drug against Burkitt lymphoma
Name of contact:
Marc Kvansakul
Email/Phone no. of contact:
m.kvansakul@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 191502
Start Year: 2002
CIA Name: Dr Helen Abud
End Year: 2004
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $436,650
Title of research award:
Using a novel gut culture system to analyse the influence of genes mutated in colon cancer on epithelial cell
growthUsing a novel gut culture system to analyse the influence of genes mutated in colon cancer on epithelial
cell growth
Lay Description (from application):
Colorectal (or bowel) cancer is a major health problem in Australia. Approximately 1 in 21 Australians will
develop the disease in his/her lifetime. The risk of bowel cancer increases with age, with the risk rising
progressively and sharply from the age of 50. Current therapies for colorectal cancer are not very effective and
the median survival for patients with this disease is poor at 7- 12 months. The development of colorectal cancer
is complex and is affected by both genetic and environmental factors. Colorectal cancer progresses through a
number of distinct pathological stages. This is thought to be the result of the progressive aquisition of
mutations in genes that normally ensure a balance between cell growth and cell death. Mutations in a number
of genes (known as APC, K-ras, p53, SMAD2, SMAD4) are commonly found in colorectal tumours. This
research is aimed at understanding how genes which are altered in colon cancer influence the growth of cells in
normal intestine. We have developed a system where normal mouse gut can be maintained and grown intact.
Genes containing the alterations found in colon cancer will be introduced into the normal gut epithelial cells
and the effects on the growth and behaviour of these cells analysed. This should improve our knowledge of
how these altered genes contribute to the development of colon cancer.
Research achievements (from final report):
The development of colorectal cancer progresses through a number of distinct pathological stages that is
thought to to be the result of mutations in genes that normally ensure a balance between cell growth and cell
death in the cells which line the intestine (epithelial cells). We have developed a novel system where normal
mouse colon can be maintained and grown in a Petri dish. Patterns of cell production, death and gene
expression are conserved in this system. We have shown that the signalling pathway activated by the growth
factor EGF is critical for the survival of epithelial cells. We have also developed a way to introduce gene
constructs to cells lining the gut by the use of a small electric shock (low voltage electroporation). This new
method allows the genetic mutations commonly observed in colon cancer to be introduced to live intestinal
epithelial cells that are accessible for observation.
Expected future outcomes:
Our novel technology can be used for a broad range of applications by researchers in the field including
functional analysis of genes implicated in colon cancer and testing of a range of external agents and drugs for
their effects on intestinal epithelial cells.
Name of contact:
Dr Helen Abud
Email/Phone no. of contact:
h.abud@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 191505
Start Year: 2002
CIA Name: A/Pr Matthias Ernst
End Year: 2004
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Oncology and Carcinogenesis
Total funding: $376,320
Title of research award:
Using the A33 antigen gene locus to generate novel mouse models of colon cancerUsing the A33 antigen gene
locus to generate novel mouse models of colon cancer
Lay Description (from application):
Colorectal (or bowel) cancer is a major health problem in Australia. It is the most common cancer reported to
Australian cancer registries and was responsible for 14% of cancer deaths in 1990, the latest year for which
national figures are available. Only lung cancer, which caused 20% of cancer deaths was a more common
cause of cancer death. Approximately 1 in 21 Australians will develop colorectal cancer during his/her
lifetime. The risk of colorectal cancer increases with age, with risk rising progressively and sharply from age
50 onwards. Like all cancers, colorectal cancer results from the progressive acquisition of mutations in genes
that normally ensure a balance between cell growth and cell death. Mutations which predispose individuals to
colorectal cancer accumulate in the epithelial cells that provide the lining to the bowel. The progression of
colorectal cancer proceeds through a number of distinct anatomical stages which can be easily recognised by
pathologists. Mutations in a number of genes (known as APC, beta-catenin, Kirsten-ras, p53, SMAD2,
SMAD4) are commonly found in colorectal tumours. Moreover, some of the mutations are highly associated
with distinct stages of colon tumour development. As yet, however, we have no real insights into how these
mutations cooperate with each other to produce full-blown (malignant) colorectal cancer. In our proposal, we
are aiming to establish colorectal cancer in mice. Our approach will be to progressively introduce mutant
genes into intestinal epithelial cells (singly and in combination) and study how they cooperate with each other
to produce benign, and ultimately, malignant tumours in the intestines of mice. This will help us to understand
which mutant genes are required for each stage in tumour development and may provide more rational
approaches to bowel cancer screening and treatment.
Research achievements (from final report):
The research conducted in the context of this project has resulted in the generation of unique and novel mouse
strains that will be of great use for the genetic dissection of the pathways that lead to sporadic colorectal
cancer. This is illustrated by the many collaborations that have been initiated based on the colon specific
A33(CRePR2) mouse generated and which is used at present in our laboratory to define the iological
consequences resulting from aberrant inactivation of b-catenin, E-cadherin or PTEN in the colonic epithelium.
We have not only generated the first reliable system to misexpress cDNAs of interest in this cellular
compartment, but we have also gained some novel and unexpected biological insights, in particular with
respect to a causal cooperative relationsship between aberrant wnt signaling and epigenetic modifications to
DNA (ie.e DNA hypermethylation).
Expected future outcomes:
As attested by the many ongoing collaborations with mice generated from this project grant, the A33(CrePR2)
and A33(TVA) mice are highly sought after strains by us and (inter)national collaborators for the tissuespecific genetic modification of intestinal epithelium in cancer and development.
Name of contact:
Matthias Ernst
Email/Phone no. of contact:
matthias.ernst@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 191520
Start Year: 2002
CIA Name: A/Pr Ian Davis
End Year: 2006
Admin Inst: Ludwig Institute for Cancer Research Grant Type: Career Development Fellowships
Main RFCD: Not Allocated
Total funding: $285,000
Title of research award:
Optimisation of cancer immunotherapy using dendritic cellsOptimisation of cancer immunotherapy using
dendritic cells
Lay Description (from application):
Not Available
Research achievements (from final report):
The immune systems of patients with advanced cancer often do not work well and cancers often develop ways
of escaping attack from the immune system. Dendritic cells (DC) are cells of the immune system that play a
key part in initiating and maintaining immune responses. It is now possible to grow DC in the laboratory,
where they can be "souped up" by treatment with various substances. Our previous work showed that activated
DC can have better effects on other cells of the immune system when tested in the laboratory. The work
supported by this award allowed us to test whether it was feasible to grow DC in numbers that would allow
them to be used in clinical trials, and whether this treatment would be safe and effective. Two clinical trials
were performed, based on work we and others have done in the laboratory and building on our experience with
other vaccine trials. We found that treatment with DC was safe, and that strong immune responses against
cancer targets could be induced. This work has also been presented at national and international conferences.
The first clinical trial has now been published and the other will be submitted for publication soon. Although it
is unlikely that this treatment will become a standard cancer treatment in the near future, we have learned
important lessons about how the immune system works against cancer and this is likely to help future
treatments to be designed more effectively.
Expected future outcomes:
No more DC trials are planned at our site, however we have taken the lessons we have learned from this work
and used them to design better vaccine strategies for future clinical trials. This work is continuing and has led
to a large international trial of one of our vaccines.
Name of contact:
Ian Davis
Email/Phone no. of contact:
ian.davis@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 234702
Start Year: 2003
CIA Name: Dr Brendan Jenkins
End Year: 2005
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Oncology and Carcinogenesis
Total funding: $447,500
Title of research award:
Genetic dissection of the gp130 signalling network; implications in the initiation of gastric cancerGenetic
dissection of the gp130 signalling network; implications in the initiation of gastric cancer
Lay Description (from application):
Stomach cancer is a major health problem in the world. It is the second most common cancer and the second
leading cause of death from cancer, behind lung cancer. In fact, approximately 10% of all new reported cancer
cases world-wide are stomach cancer. The risk of stomach cancer increases with age, with risk rising
progressively and peaking at about 60 years of age. Men are affected twice as often as women Like all cancers,
stomach cancer results from the progressive acquisition of mutations in genes that normally ensure a balance
between cell growth and cell death. Mutations which predispose individuals to stomach cancer accumulate in
the epithelial cells that provide the lining to the stomach. The progression of stomach cancer proceeds through
a number of distinct anatomical stages which can be easily recognised by pathologists. Mutations in a number
of genes (known as Kirsten-ras, p53) are commonly found in stomach tumours. Moreover, some of the
mutations are highly associated with distinct stages of tumour development. As yet, however, we have no real
insights into how these mutations cooperate with each other to produce full-blown (malignant) stomach cancer.
In our proposal, we are aiming to establish stomach cancer in mice. Our approach will be to use an existing
animal model which is predisposed to stomach cancer. We will progressively introduce mutant genes into
stomach epithelial cells and study how they cooperate with each other to produce benign, and ultimately,
malignant tumours in the stomach of mice. This will help us to understand which mutant genes are required for
each stage in tumour development and may provide more rational approaches to stomac cancer screening and
treatment.
Research achievements (from final report):
Stomach cancer is the second most common cancer and the second leading cause of death from cancer in the
world. The risk of stomach cancer increases with age, with risk rising progressively and peaking at about 60
years of age. Like all cancers, stomach cancer results from the progressive acquisition of mutations in genes
that normally ensure a balance between cell growth and cell death. Although mutations in some genes are
commonly found in stomach tumours, we have no real insights into how these mutations cooperate with each
other to produce full-blown (malignant) stomach cancer., Our studies have made several substantial
contributions to understanding the role of Stat3, a protein found in all cells including stomach epithelial cells,
in stomach tumours. We showed that, in mice, hyperactive Stat3 (i.e. increased Stat3 activity) shuts down a
vital controller of stomach cell growth, called TGF beta, and this allows tumours to form, and this mechanistic
link is a world-first. Importantly, lowering Stat3 hyperactivity in these mice actually suppresses stomach
tumour formation by allowing TGF beta to function normally, and this occurs without affecting Stat3's other
important roles in the body. Also, the gene differences identified in human stomach tumours are similar to
those we would predict if the same thing, Stat3 hyperactivity shutting down TGF beta, happens in humans. So
this is also the first time a connection between stomach cancer and this signaling pathway has been made.
Expected future outcomes:
For several years accumulating evidence has suggested that Stat3 hyper-activity is involved in breast, head and
neck, and, prostate cancers. Our research identifying a role of Stat3 hyper-activity in stomach tumours further
provides a compelling case for investigating the development of therapies targetting Stat3 in these, and
potentially other, cancers.
Name of contact:
Brendan Jenkins
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
brendan.jenkins@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 234708
Start Year: 2003
CIA Name: Dr Graham Lieschke
End Year: 2005
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Genetic Development (incl. Sex Determination)
Total funding: $425,250
Title of research award:
Identification of genes important in myeloid and haemopoietic development by genetic screening in
zebrafishIdentification of genes important in myeloid and haemopoietic development by genetic screening in
zebrafish
Lay Description (from application):
Zebrafish have emerged as a powerful experimental model in developmental genetics. Their favourable
attributes include their reproductive biology, the optical clarity of embryos, and the accessibility of embryos for
experimental procedures. Previous studies overseas have recovered over 1500 strains of zebrafish with
inherited diseases due to induced mutations in about 500 genes. Many of these zebrafish have abnormalities of
unexpected precision and are leading to new genes with novel specialized functions. About 50 mutant zebrafish
strains exist in which red blood cell development is perturbed - this was easily recognized because the
transparency of embryos enabled lack of blood be easily seen. Our new studies aim primarily to recover mutant
zebrafish with disorders of white blood cell formation. We have identified methods to recognize failure of
white blood cell formation in zebrafish, and will employ these methods to look for inherited disorders that
specifically affect white blood cell development in a process called genetic screening. Fish with different sets
of randomly mutated genes will be systematically screened to identify those with abnormal white blood cell
development. We have tested our approach and identified several mutants affecting white blood cell
development. Once these new strains of fish are identified, we will find the genetic lesion responsible for the
abnormality in several of the most interesting strains by gene mapping and positional cloning. Hence, the
mutant zebrafish identified in the screen will eventually lead to the discovery of new genes important in white
blood cell growth and development. The fish themselves will provide insights into the causes of congenital
diseases of white blood cells. Since many genes involved in early development are also important in cancer, we
believe that newly identified genes will also help understand the causes of abnormal growth of white blood
cells in leukaemia.
Research achievements (from final report):
A genetic screen collecting a group of 20 zebrafish mutants with defects affecting white blood cell production
was undertaken. These mutants are animal models of human genetic defects in white blood cell development,
collected at random and unbiased by prior presumptions. The ultimate goal is to learn new things about how
white blood cells grow, providing a basis for understanding congenital white blood cell failure diseases, and
also for understanding what goes wrong when white blood cell growth goes out of control in leukaemia. Under
this project grant, the mutants were collected and underwent a preliminary descriptive analysis. So that the
defective gene underpinning their problems with white blood cell growth could be identified, they were
mapped to a location on the genomic map. Several of the mutant genes have been identified. One mutant was
studied in detail and provided new insight into how signals from a particular receptor were involved in the
formnation of the first white blood cells in emrbyonic development. A new hypothesis about the role of this
signalling pathway in mammalian white blood cell development was proposed. This work is significant
because it will lead to unexpected new insights into the biology of blood cell development that will help
understand and diagnose hereditary disease, and which in due course will also provide insights relevant to
leukaemia diagnosis and treatment.
Expected future outcomes:
The mutants will provide the basis for many years of work. The remaining mutants will be mapped, the
defective genes identified, and their role in blood cell development studied, resulting in a better understanding
about the genetic regulation of white blood cell development.
Name of contact:
NHMRC Research Achievements - SUMMARY
Graham Lieschke
Email/Phone no. of contact:
lieschke@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 234710
Start Year: 2003
CIA Name: A/Pr Weisan Chen
End Year: 2005
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Cellular Immunology
Total funding: $234,750
Title of research award:
The mechanisms of establishing, maintaining immunological memory and immunodominance hierarchyThe
mechanisms of establishing, maintaining immunological memory and immunodominance hierarchy
Lay Description (from application):
The hallmark of the adaptive immune response is the development of specific immunological memory
following the first confrontation with a microorganism. Memory T cells are capable of responding rapidly
upon subsequent exposure to the same microbes thus providing protective immunity. This proposal aims to
investigate how cytotoxic T cells establish memory following their primary encounter with microorganisms.
The proposal will dissect the relationship between memory T cell formation and the amount/length of antigen
exposure; and the influence on memory induction from various immune modulators (cytokines) at the time of
antigen encounter. Using a range of sophisticated detection methods, very early memory T cells will be
identified in the primary response and tracked through their differentiation into long-term memory pool.
Experiments will determine how T cells against particular determinants are selected from the primary immune
response, retained in the memory pool and recalled in the subsequent challenges. The properties of antigen
processing of various determinants will be correlated with the immunodominance hierarchy in the primary and
memory response.
Taken together the proposed project is central to understanding how memory T cells are
created and what rules govern their stability. The project is highly relevant to vaccine design against tumours
and pathogens
Research achievements (from final report):
We not only conducted most of the proposed work but also made novel observations in related projects. We
have demonstrated the following: 1.) T cells specific to different epitopes can compete during a memory
response. 2.) This competition is likely linked through accessing the same antigen-presenting cells (APC). 3.)
Memory T cell formation is epitope dependent. 4.) Different immunodominant CD8+ T cell epitopes and
responding T cell repertoires are differentially affected by the deficiency of immunoproteasome subunits; 5.)
Some immunodominant T cell epitope can be very sensitive to these subunit deficiencies; 6.) Enhanced antigen
processing/presentation might be able to overcome or compensate some T cell repertoire defects and convert an
immunosubdominant response into an immunodominant one. These findings need to be taken into
consideration in future vaccine design.
Expected future outcomes:
We will continue to explore the contribution of the immunoproteasome to immune responses in a in vivo
setting. This will hopefully not only confirm many of the previous findings based on in vitro studies, but also
allow us to assess the real importance of the immunoproteasome in anti-viral and anti-tumoral immune
response, or even other roles potentially not directly relating to antigen processing
Name of contact:
Weisan Chen
Email/Phone no. of contact:
weisan.chen@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 280900
Start Year: 2004
CIA Name: A/Pr Steven Stacker
End Year: 2008
Admin Inst: Ludwig Institute for Cancer Research Grant Type: Programs
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $2,589,101
Title of research award:
The biology & therapeutic manipulation of Lymphatic vessels in cancer & lymphedemaThe biology &
therapeutic manipulation of Lymphatic vessels in cancer & lymphedema
Lay Description (from application):
This proposal brings together a team of researchers from diverse backgrounds who have
already made important discoveries about the molecular control of the lymphatic system in
normal physiology and cancer. The lymphatic vasculature consists of a network of vessels in
organs and tissues that is critical for the regulation of tissue fluid volume and immune
function. The lymphatics are also important for the metastatic spread of cancer, as they
provide a route by which tumour cells spread to distant sites in the body, and for lymphedema,
a condition in which lymphatic dysfunction leads to swelling of tissues. This program will
explore the molecular mechanisms that control the growth and differentiation of the lymphatic
vessels. It will greatly enhance our understanding of lymphatic vessel growth
(lymphangiogenesis) and generate a range of reagents for stimulating or inhibiting this
process. These reagents will be tested in animal models for their capacity to modulate
lymphatic function in the context of cancer and lymphedema.
Research achievements (from final report):
This program of research enhanced our understanding of the lymphatic system and its role in human disease. It
involved the discovery and characterization of molecules which control the growth and development of the
lymphatic system, and of the specialised endothelial cells which line lymphatic vessels. Our studies also
facilitated the development of reagents with potential use for the treatment of human diseases in which the
vascular network has been dysregulated. One example is the protein vascular endothelial growth factor-D
(VEGF-D) which is now being used to promote the longevity of vascular access grafts required by patients
receiving dialysis treatment - this agent is currently entering a Phase III clinical trial. Other reagents such as
inhibitory antibodies to VEGF-D are being developed for clinical evaluation as inhibitors of the growth and
spread of human cancer. Some of these clinical developments are being carried out in partnership with an
Australian biotechnology company, Vegenics Ltd., which was founded based on discoveries that arose from
this research program. The Program also provided an excellent educational and training resource for young
scientists and clinicians around Australia wanting to investigate the role of the lymphatics in human disease.
Expected future outcomes:
Our study of the lymphatic network will reveal many links to human diseases including cancer and
lymphoedema. The generation of reagents that interfere with major growth and development pathways of the
lymphatic system will provide an opportunity to develop therapeutic and diagnostic approaches for these
diseases.
Name of contact:
Steven Stacker
Marc Achen
Email/Phone no. of contact:
steven.stacker@ludwig.edu.au
marc.achen@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 280902
Start Year: 2004
CIA Name: Dr Kenneth Harder
End Year: 2006
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Immunology not elsewhere classified
Total funding: $381,000
Title of research award:
An analysis of the Lyn tyrosine kinase in the regulation of hematopoiesis and tumourigenesis.An analysis of
the Lyn tyrosine kinase in the regulation of hematopoiesis and tumourigenesis.
Lay Description (from application):
The Lyn kinase is an enzyme that is involved in relaying information across the cell membrane. It is a member
of a family of genes that have been implicated in tumour development. Lyn is expressed in blood cells and it is
involved in a variety of immunological responses. To further our understanding of the role of this enzyme in
the context of the whole animal, we have generated two strains of mice, one that is unable to make Lyn protein
(Lyn-deficient mice) and one that expresses an activated form of the Lyn enzyme (Lyn-up mice). Our previous
studies have shown that Lyn-deficient mice have enhanced blood cell formation (hematopoiesis) and develop
white blood cell tumours with age, whereas Lyn-up mice show no propensity to develop tumours. In this
study we will examine in detail the role that Lyn plays in blood cell formation and tumourigenesis, and we will
identify the pathways that underlie the phenotypes in Lyn-deficient mice. On completion of these studies we
will have catalogued the molecules and pathways regulated by Lyn, and have an understanding of how Lyn
functions in regulating development of specific populations of blood cells, and in suppressing or promoting
tumour development.
Research achievements (from final report):
The studies undertaken in this research proposal have provided significant insights into the role that the Lyn
tyrosine kinase plays in growth factor signalling and haematopoiesis. We have shown that deficiency of Lyn
leads to a progenitor cell defect that results in exacerbated erythropoiesis and myelopoiesis, leading to
hyperplasia of the erythroid and myeloid compartments and eventually to myeloid tumours. Our analyses of
Lyn-deficient mice demonstrate that this kinase plays a critical role in haematopoiesis and tumourigenesis,
primarily as a negative regulator. We have now begun to identify Lyn-dependent substrates and signaling
pathways that are critical to the regulation of haematopoiesis and therefore potential targets for therapeutic
intervention.
Expected future outcomes:
Our studies have clearly shown that Lyn is an important regulator of haematopoiesis and tumourigenesis.
Identifying Lyn-dependent signaling proteins and pathways is the critical next step, as these may prove to be
vaulable therapeutic targets in blood cell disorders.
Name of contact:
Margaret Hibbs
Email/Phone no. of contact:
Margaret.Hibbs@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 280905
Start Year: 2004
CIA Name: A/Pr Margaret Hibbs
End Year: 2009
Admin Inst: Ludwig Institute for Cancer Research Grant Type: Established Career Fellowships
Main RFCD: Autoimmunity
Total funding: $639,500
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
During the course of this fellowship, two major themes were followed. The first revolved around improving
our understanding of the mechanisms behind autoimmune disease development using a well established animal
model of SLE, with the ultimate goal of identifying potential points of therapeutic intervention. Towards this
goal, we have shown that alterations to the inflammatory environment can alter the course of the disease. We
have found that the proinflammatory cytokine IL-6 plays a major role in converting the disease in Lyndeficient mice to a pathogenic state. In the absence of IL-6, autoreactive B cells are present, but it is the IL-6dependent inflammatory environment that they engender that dictates their disease-causing potential. In
addition we have also found that alterations in signaling pathways can lead to accelerated or diminished disease
development in Lyn-deficient mice. Loss of the negative regulators SHIP-1 or SHP-1 can exacerbate disease,
while loss of PI3K-p110δ causes a dampening of the myeloid compartment, diminished inflammation and
attenuated autoimmunity. These data support the use of IL-6-antagonists and p110δ-PI3K inhibitors in SLE
therapy., Our second goal involved the characterisation of alveolar macrophages in models of lung
inflammation (SHIP-deficient, Lyn-gain-of-function), since lung macrophages are highly implicated in the
development and progression of severe lung diseases such as COPD and lung cancer. We have found
dramatically increased numbers of highly activated alveolar macrophages in both strains, which are the subject
on on-going studies. We have recently generated compound mutants in relevant signaling pathways and have
begun to define their contribution to the lung phenotype. This work is still on-going.
Expected future outcomes:
There have been numerous unsuccessful clinical trials for new agents in the treatment of the autoimmune
disease SLE. Our future studies are aimed at assessing the therapeutic potential of IL-6 antagonists and PI3K
inhibitors in this debilitating disease.
Name of contact:
Margaret Hibbs
Email/Phone no. of contact:
Margaret.Hibbs@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 280912
Start Year: 2004
CIA Name: Prof Antony Burgess
End Year: 2008
Admin Inst: Ludwig Institute for Cancer Research Grant Type: Programs
Main RFCD: Medical Biochemistry: Proteins and Peptides
Total funding: $7,115,543
Title of research award:
Colon Cancer: Receptors, Signalling and TherapeuticsColon Cancer: Receptors, Signalling and Therapeutics
Lay Description (from application):
This program aims to understand the biochemical and biological basis of colorectal cancer, a major
cause of cancer deaths in Australia. The Chief Investigators have extensive experience in the
analysis of the molecular defects in colorectal cancer cells and have already developed new drugs to
treat successfully experimental colon tumours in animals. During this research program, we will
explore these systems further, concentrating on the identification of novel inhibitors of colon cancer
cell growth, survival and movement. Newly developed instruments and techniques will allow us to
identify and detect the critical steps during the development of colorectal cancer and to design potent
drugs to fight the disease. We have experience in conducting novel clinical trials in colon cancer and
have developed imaging techniques for monitoring the effectiveness and safety of new anti-cancer
drugs. Our collective scientific experience and ability to work in the clinic provides a unique
opportunity for developing more effective treatments for colorectal cancer patients.
Research achievements (from final report):
Our program grant has allowed us to investigate the role of the EGFR in colon cancer and brain tumours.
Overexpression and/or activiation of the EGFR is a characteristic of many carcinomas and several cancer
treatments now target the EGFR. However, current reagents neutralize both normal and tumour associated
EGFR. We have characterized an antibody mab806 which selectively targets truncated, amplified (overexpressed) or activated EGFR on tumour cells. Using structural biology and biosensor analyses we have
determined that on tumour cells there is a distinct, regional reorientation of the EGFR in the region of the
mab806 epitope. This may be caused by incomplete formation of disulphide bonds and/or changes associated
with ligand induced aggregation. This antibody (mab806) has been licensed for development as an anti cancer
agent by a major pharmaceutical company. Our research has led to a deeper understanding of the role of the
wnt/apc/axin/beta-catenin system in colon cancer. Our results indicate that it is clear that truncation of apc
increases autocrine wnt signalling and that this signalling is directly associated with tumour progression. Our
team analysed the proteins secreted by colorectal cancer cells. We identified many soluble secreted proteins,
apparently specific to colorectal cancers. We also detected exosomes, released by colorectal cancer cell lines,
which appeared typical of colorectal cancer. These proteins were also detected in the blood of mice carrying
human colorectal cancer xenografts. We have identified approximately 20 proteins which have the ptotential to
identify people who are likely to have colon cancer. We are now working with a diagnostic company to
develop the reagents to test for these proteins in the blood and/or faeces of humans at higher risk of colon
cancer.
Expected future outcomes:
We expect that a new anti-cancer agent (mab806) will be developed for use in combination with conventional
chemotherapy or other targetting agents when treating colon cancer or brain tumours. We are hopeful that one
or more of the colon cancer specific proteins identified through proteomic analysis will lead to an improved
early detection test for colorectal cancer.
Name of contact:
Tony Burgess
Email/Phone no. of contact:
Tony.Burgess@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 280916
Start Year: 2004
CIA Name: A/Pr Joan Heath
End Year: 2006
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Genetic Development (incl. Sex Determination)
Total funding: $465,750
Title of research award:
Identification of genes regulating vertebrate intestinal developmentIdentification of genes regulating vertebrate
intestinal development
Lay Description (from application):
Colorectal cancer (CRC) causes 14 per cent of all cancer deaths in Australia. While early detection improves
survival rate, nearly half of all CRC patients succumb to the disease within five years. In general, metastatic
CRC is resistant to chemotherapy and radiotherapy and new therapies are required. An increased knowledge of
the processes that contribute to the malignant state is likely to suggest new targets for treatment. CRC, like all
cancer, is the result of genetic abnormalities (mutations) that are acquired over the course of a lifetime.
Together the mutated genes produce changes in cell behaviour in processes such as growth, migration,
angiogenesis (the ability to attract a blood supply) and cell death. All of these processes are active during
normal development of a vertebrate organism, but are generally shutdown in the adult state, except in cancer.
In this study, we propose to identify a set of genes that control the development of the intestine in a small
tropical fish, the zebrafish. Zebrafish are vertebrate organisms, closely related to mice and man. Essentially all
the pathways regulating development are conserved in the three species. The zebrafish offers several
advantages: they are small, easy to breed, cheap to maintain and, most importantly, their embryos are
transparent, making it possible to visualise development in live embryos in a simple microscope. Our project
will use a panel of mutant strains of zebrafish that have an array of visible abnormalities in intestinal
development. The abnormalities were induced using a chemical that produces single base pair changes in
DNA. An established technique called positional cloning will allow us to identify the genes in which the
mutations have been introduced, and provide a genetic explanation for the intestinal abnormalities. Upon
identification of the mutated genes, our ultimate aim will be to test whether they also play a role in the
development of CRC, using mouse models and human tissues.
Research achievements (from final report):
Colorectal cancer (CRC) causes more cancer deaths in Australia than any other cancer. While early detection
improves survival rate, nearly half of all CRC patients succumb to the disease within five years. CRC, like all
cancer, is the result of genetic abnormalities (mutations) that are acquired over the course of a lifetime.
Together the mutated genes produce changes in cell behaviour in processes such as growth, migration,
angiogenesis (the ability to attract a blood supply) and cell death. In this study we identified a set of genes that
control the development of the intestine in a small tropical fish, the zebrafish. Zebrafish are vertebrate
organisms, closely related to mice and man. Our project was built around a panel of mutant strains of zebrafish
that exhibit an array of visible abnormalities in intestinal development. The abnormalities were originally
induced using a chemical (ethylnitrosurea) that produces single base pair changes in DNA. An established
technique called positional cloning allowed us to identify the genes underlying four intestinal mutants, thereby
providing a genetic explanation for the development of the intestinal abnormalities. The next stage of the
project is to test whether theses genes also contribute to the development of CRC, using mouse models and
human tissues.
Expected future outcomes:
The genes that we have identified play indispensable roles in vertebrate intestinal development. In the next
phase of our study we will determine whether the expression and behaviours of these genes are perturbed in the
development of colorectal cancer, and whether they could be targeted for treatment of the disease.
Name of contact:
Joan K Heath
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
joan.heath@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 280918
Start Year: 2004
CIA Name: Dr Andrew Clayton
End Year: 2006
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $490,750
Title of research award:
Fluorescence analysis of the EGFreceptor signalling networkFluorescence analysis of the EGFreceptor
signalling network
Lay Description (from application):
Receptors are cell-surface molecules that enable the cell to receive chemical messages from the outside
environment and transmit these signals to the inside of cell. These messages tell the cells to grow, divide or die.
The Epidermal Growth Factor Receptor is linked to a variety of cell signalling pathways that are critical to the
normal functioning of cells. Conversely, abberations in Epidermal Growth Factor-mediated cell signalling
leads to many types of cancers. A basic understanding of how the receptor is turned off or on is essential to
designing drugs that can specifically inhibit its hyperproliferative response. High resolution structures of a key
part of the Epidermal Growth Factor Receptor have identified several structural forms of the receptor that are
providing valuable clues as to the structural basis for receptor activation. Armed with this information and
advanced microscopic imaging technology we are in the unique position to probe receptor activation in living
cells. This project seeks to determine which structural form of the receptor is responsible for transmission of
cellular messages and how it is impaired in cancerous cells.
Research achievements (from final report):
Cell surface receptors play an essential role in transmitting information from the outside of the cell to the cell
interior. When the signals from the outside of the cell are misinterpreted or incorrectly sent disease states such
as cancer can be the result. The epidermal growth factor receptor is one receptor that when overproduced or
truncated is associated with the progression of cancer. Using new microscopies together with geneticallyencoded fluorescent tags we are investigating the activation process od the EGF receptor in normal cells and
how this mechanism is bypassed in tumour cells. Our analysis has revealed a new mechanism of EGF receptor
activation that involves inactive dimers pairing up to form tetramers in the presence of the epidermal growth
factor ligand. In normal cells movement of dimers to form a tetramer is required to activate the receptor.
However, in tumour cells, we found that the EGF receptor was already in a pre-tetramerised state. This
suggests that in the tumour cell the receptor is "ready-to-go" and doesn't need to constraints of bringing two
receptor dimers together to activate the receptor. Current therapeutics are designed to act agaisnt the EGF
receptor dimer but this form of the receptor is already present on the cell surface in an incative form. The
implications of our novel findings are that therapeutics should stop the formation of or disrupt EGFR tetramers
in order to inhibit abberrant signalling from the EGF receptor.
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 280920
Start Year: 2004
CIA Name: Dr Andrew Clayton
End Year: 2008
Admin Inst: Ludwig Institute for Cancer Research Grant Type: Career Development Fellowships
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $444,500
Title of research award:
Molecular initiation of the erbB signaling network.Molecular initiation of the erbB signaling network.
Lay Description (from application):
Not Available
Research achievements (from final report):
Cell surface receptors play an essential role in transmitting information from the outside of the cell to the cell
interior. When the signals from the outside of the cell are misinterpreted or incorrectly sent, disease states such
as cancer can be the result. The epidermal growth factor receptor is one receptor that, when overproduced or
truncated, is associated with the progression of cancer. Using new microscopies together with geneticallyencoded fluorescent tags we are investigating the activation process of the EGF receptor in normal cells and
how this mechanism is bypassed in tumour cells. Our analysis has revealed a new mechanism of EGF receptor
activation that involves inactive dimers pairing up to form tetramers in the presence of the epidermal growth
factor ligand. In normal cells movement of dimers to form a tetramer is required to activate the receptor.
However, in tumour cells, we found that the EGF receptor was already in a pre-tetramerised state. This
suggests that in the tumour cell the receptor is "ready-to-go" and doesn't have the constraints of bringing two
receptor dimers together to activate the receptor. Current therapeutics are designed to act against the EGF
receptor dimer but this form of the receptor is already present on the cell surface in an inactive form. The
implications of our novel findings are that therapeutics should stop the formation of or disrupt EGFR tetramers
in order to inhibit aberrant signalling from the EGF receptor. In the broader context of receptor biology, it
implies that there are different receptor oligomeric states that confer different properties in terms of the cellular
response. The implication of this new mechanism is that a new interface is involved that provides a potential
target for drug therapy.
Expected future outcomes:
The ultimate benefits will be more selective drugs to help cancer patients with tumours that are driven by the
EGF receptor pathway.
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 280927
Start Year: 2004
CIA Name: A/Pr Edouard Nice
End Year: 2006
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Development Grants
Main RFCD: Diagnostic Applications
Total funding: $267,500
Title of research award:
Development of a novel biosensor using magnetically amplified luminescence for the early detection of
cancerDevelopment of a novel biosensor using magnetically amplified luminescence for the early detection of
cancer
Lay Description (from application):
Cancer is often not detected until it has invaded surrounding tissues and spread to other organs. Current
treatment is then often ineffective, and prognosis poor. Early detection of cancer is therefore essential for
improved disease management. Such methods must be cheap, non-invasive, and rapid with high sensitivity and
specificity. We are investigating a new biosensor technology that satisfies these criteria. This method uses
magnetically amplified luminescence for the detection of low levels of cancer cells in clinical samples (urine,
faeces, blood, biopsy), using telomerase as a marker.
Research achievements (from final report):
This grant has enabled us to develop novel biosensor assays for telomerase and other potential cancer
biomarkers and apply them to clinical samples. The telomerase assay, which is amenable to automation,
demonstrated high sensitivity and specificity in a pilot study involving a small clinical cohort of bladder cancer
patients and non-diseased controls, making it of potential benefit as a first line assay for bladder cancer
detection and monitoring (92.9 % sensitivity and 100 % specificity). We have also conducted preliminary
studies on the detection of colonocytes in faecal samples from patients with colon cancer. Colonocytes were
recovered from faecal homogenates using magnetic bead technology. 60%+ recovery was achieved with
control samples spiked with human colon cancer cells. Positive telomerase assays have been obtained with a
limited number of samples from patients with colon cancer. , , We have also successfully established amplified
luminescence assays for the epidermal growth factor receptor (EGFR) and the cancer-testis antigen NY-ESO-1.
These assays have ng/ml sensitivity. The EGFR assay has been validated using a novel proteomics strategy.
Both assays have been used with a limited number of clinical samples from patients with colon cancer and
melanoma respectively. , , Two new patents have arisen from these studies.
Expected future outcomes:
We have successfully transferred these assays to our commercial partner, Sienna Cancer Diagnostics. They are
setting up a new laboratory at Bio21 to enable them to take the assays to commercialisation. The quality of the
data we have generated has been fundamental to fund raising and discussions with several major biotech
companies.
Name of contact:
A.Prof. Edouard Nice
Email/Phone no. of contact:
ed.nice@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 331004
Start Year: 2005
CIA Name: A/Pr Matthias Ernst
End Year: 2009
Admin Inst: Ludwig Institute for Cancer Research Grant Type: Established Career Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $595,500
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
My innovative approach to genetically dissect complex intracellular signalling in the whole mouse has
provided novel and unexpected insights into the hitherto unsuspected role for Stat3, in particular in the context
of the regulation of epithelial homeostasis in the gastrointestinal tract. Specifically, the research funded through
this fellowship has enabled me to provide irrefutable evidence for Stat3 playing a causal role in functionally
linking inflammation to tumour progression. The resulting work culminated in the publication of full-length
articles in Nature Medicine (x1), Nature Immunology (x2), Cancer Cell (x1) and many other high impact
journals.
Expected future outcomes:
The molecular insight gained through this work has resulted in several collaborations with pharamceutival
companies (incl. Ely-Lilly, Novartis) and, most prominently in a collaborative research agreement with CSL
Ltd for the development of anatgonists that mediate inflammation dependent on Stat3 activation within the
tumour microenvironment.
Name of contact:
Matthias Ernst
Email/Phone no. of contact:
matthias.ernst@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 331005
Start Year: 2005
CIA Name: A/Pr Matthias Ernst
End Year: 2008
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $667,000
Title of research award:
The Role of TGF-beta Signaling in Suppression of Stat3-mediated TumorigenesisThe Role of TGF-beta
Signaling in Suppression of Stat3-mediated Tumorigenesis
Lay Description (from application):
Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of
several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor
molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to
understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach
mining cells. Our proposal combines the expertise of the two investigators in signal transduction and the
making of genetically modified mouse models. These strategies will be employed to specifically address in the
laboratory mouse the function of two specififc signaling cascades, called Stat3 and TGF-beta. The
identification of detailed description by which these molecules causally relate to cancer formation will provide
clear and specific molecular targets for future therapies to treat various cancers, including those of the stomach.
Research achievements (from final report):
We generated several compound mutant mice carrying the original hyperactivatable gp130Y757F mutant allele
together with null alleles for Smad3 or a conditional null allele for Smad4. In particular, the compound
gp130Y757F;Smad3KO mice show a surprising susceptibility to pulmonary fibrosis, suggesting a hitherto
unknown novel role for Stat3 to trigger this disease independently of the TGFb pathway. We have confirmed
the capacity of Stat3 hyperactivation to transcriptionally activate expression of the Smad7 gene in a variety of
cell lines and tissues. Furthermore, we generated muatnt mice in which Stat3 is specifically hyperactivated in
intestinal epithelium and found that these resulted in increased tumour formation in the ApcMin mouse of
intestinal tumorigenesis, suggesting epistatic interaction between aberrant Stat3 and canonical Wnt-signaling. ,
We also have identified EGFR as a tumor-related upstream activator of Stat3, in tumors cells over-expressing
EGFR. We show activation of tumor-associated over-expression of EGFR desensitizes TGFb signaling and its
cytostatic regulation through Smad7 induction. In normal and tumor cells, reduction of TGFβ-mediated Smad2
activation and Smad3 target gene activation was observed when EGFR was over-expressed, but not in cells
which expressed wild-type levels of expressed EGFR. We identified Stat3 as a signaling molecule activated
specifically and persistently by over-expressed EGFR, but not by normal levels. Importantly, Stat3 is
responsible for the modifying TGFb sensitivity, since its knockdown by siRNA restored TGFb sensitivity.
Furthermore, over-expressed EGFR, through Stat3 activates Smad7 promoter activity, which suppresses TGFb
signaling. Consequently, cells were re-sensitized to TGFb reduced using Smad7 siRNA. Therefore we establish
a novel EGFR-/Stat3-/Smad7-/TGFb-signaling axis where tumor-associated over-expression of EGFR in
epithelial cells partially promotes growth through suppression of TGFb signaling.
Expected future outcomes:
We are currently further investigating the molecular mechanism underlying the functional cooperation between
the gp130/Stat3 pathway and the wnt/b-catenin pathway in gastrointestinal tumorigenesis . These findings are
therefore likely to have major implications on the identification of novel therapeutic targets.
Name of contact:
Matthias Ernst
Email/Phone no. of contact:
matthias.ernst@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 381402
Start Year: 2006
CIA Name: A/Pr Margaret Hibbs
End Year: 2008
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Oncology and Carcinogenesis
Total funding: $469,526
Title of research award:
Tumour suppressor networks: the role of SHIP-1 and Lyn in suppressing haematopoietic tumoursTumour
suppressor networks: the role of SHIP-1 and Lyn in suppressing haematopoietic tumours
Lay Description (from application):
Haematopoietic malignancies kill a large number of Australians each year. Improving our understanding of the
molecular mechanisms that underlie these diseases is essential for the design of more effective treatments. Lyn
and SHIP-1 are enzymes that are found in blood cells, and both participate in terminating cellular responses.
As such, these enzymes are critically important for maintaining stability in the immune system. While these
enzymes have unique roles, we also have good evidence that in some instances Lyn and SHIP-1 participate in
the same biochemical pathway. We have created mice that are unable to make Lyn protein, and have found
that these mice develop blood cell tumours. Mice lacking SHIP-1 develop a number of haematological defects,
but die at a young age due to an inflammatory lung condition, making an assessment of the role of SHIP-1 in
age-dependent tumour development difficult. We now wish to study the role of SHIP-1 in tumour
development, by generating mice that lack SHIP-1 in specific white blood cell compartments. We are also
investigating how SHIP-1 and Lyn cooperate in tumour suppression, and we have recently generated mice that
simultaneously lack both SHIP-1 and Lyn. Preliminary studies indicate that compound mutant mice develop
multiple haematological malignancies. We will fully characterize tumour development in these animals, and
determine the molecular basis for this pathology. We will focus on two pathways that have been previously
implicated in oncogenesis. These studies will improve our insight into how Lyn and SHIP-1 cooperate in
blood cell development, cellular homeostasis and oncogenesis, and add to our biological and biochemical
understanding of tumour suppressor networks.
Research achievements (from final report):
The studies undertaken in this research proposal have shown that Lyn and SHIP-1 cooperate in suppression of
haematopoietic tumours, but we have found that genetic background and modifying loci both play an important
role in this phenotype. Mice on the BALB/c background develop striking and widespread lymphadenopathy
and extensive splenomegaly, composed of dysplastic B lymphocytes and myeloid cells - a phenotype that is
100% penetrant by 14 wks. This phenotype is significantly moderated in C57BL/6 background Lyn-/-SHIP-1-/mice. While further studies are underway to fully define this phenotype, they clearly underscore the
significance of genetic background in animal studies of disease., As an adjunct to this research proposal we
have also gained significant insights into the role that the SHIP-1 inositol phosphatase plays in B cell signaling
and autoimmune disease development. We have shown that loss of SHIP-1 is a model of spontaneous
autoimmune disease in mice, but the severity of disease is dependent on mouse genetic background. These
results highlight the importance of genetic background in animal studies of autoimmune disease.
Expected future outcomes:
Our studies have clearly shown that Lyn and SHIP-1 are important regulators of B cell signaling and
tumourigenesis. Identifying Lyn and SHIP-1-dependent signaling proteins and pathways is the critical next
step, as these may prove to be valuable therapeutic targets in the treatment of autoimmune disease or blood cell
cancers.
Name of contact:
Margaret Hibbs
Email/Phone no. of contact:
Margaret.Hibbs@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 381411
Start Year: 2006
CIA Name: Dr Oliver Bernhard
End Year: 2010
Admin Inst: Ludwig Institute for Cancer Research Grant Type: Early Career Fellowships (Australia)
Main RFCD: Diagnostic Applications
Total funding: $278,065
Title of research award:
Analysis of Biomarkers associated with Colorectal CancerAnalysis of Biomarkers associated with Colorectal
Cancer
Lay Description (from application):
Not Available
Research achievements (from final report):
This research aimed to identify candidate biomarkers for the detection of colorectal cancer. The incidence of
colorectal cancer is approximately 1 in 23 and this cancer has a high mortality rate due to it often being
detected at an advanced or late stage. In this research, an approach was developed using colorectal cancer cell
lines and animal models to generate a shortlist of potential soluble biomarkers, shed from the cell lines and
circulating in the animals, which could be used to detect colorectal cancer at an earlier stage, where it is more
easily treatable. Blood-based assays were developed for some of the candidate biomarkers and will be further
evaluated for clinical testing. A collaborative research relationship with the company Biosite (now Inverness)
was developed to exploit the six markers identified in my research. Inverness has the ability to progress this
research to clinical use for early detection of colorectal cancer should my biomarkers prove to be selective and
specific in patient samples.
Expected future outcomes:
, Clinical evaluation of the selected biomarkers will be performed by Biosite/Inverness. The strategy employed
in this research may be used for biomarker development in other cancers.
Name of contact:
Oliver Bernhard
Email/Phone no. of contact:
oliver.bernhard@starpharma.com
NHMRC Research Achievements - SUMMARY
Grant ID: 433607
Start Year: 2007
CIA Name: A/Pr Joan Heath
End Year: 2011
Admin Inst: Ludwig Institute for Cancer Research Grant Type: Established Career Fellowships
Main RFCD: Genetics not elsewhere classified
Total funding: $559,560
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a molecular/cell biologist studying genetic regulation of vertebrate intestinal development and human
colon cancer
Research achievements (from final report):
The zebrafish is a small aquatic organism that is ideal for genetic studies. Zebrafish are vertebrates, which
means that they are extremely closely related, genetically, to mammals, including humans. By conducting a socalled "genetic screen" this organism can be used to identify genes that are responsible for directing processes
that are crucial for the success of all vertebrate animals, including their development. During the duration of
this Fellowship award, the Fellow and her team successfully used zebrafish embryos to identify genes that play
a crucial role in the growth and division of cells lining the intestine during a period in early development when
they are growing extremely rapidly. Eight genes that are indispensible for normal intestinal development were
discovered. Interestingly, these genes were found to play well-characterised roles in multiple complex cellular
functions, such as nuclear pore formation, ribosome biogenesis, gene transcription, mRNA splicing and
intracellular protein trafficking. Because these genes and cellular functions are likely to be essential for the
growth of intestinal cancer cells as well as developing cells, current investigations in the Fellow's laboratory
are designed to investigate whether these genes, and the processes they are involved in, could provide new
targets for cancer therapy.
Expected future outcomes:
It is expected that one (or more) of the identified genes or cellular processes may represent a valid target for
colorectal cancer therapy. Our studies have resulted in several publications in internationally respected
journals, with several more in the pipeline.
Name of contact:
Joan K Heath
Email/Phone no. of contact:
joan.heath@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 433613
Start Year: 2007
CIA Name: A/Pr Joan Heath
End Year: 2009
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Therapies and Therapeutic Technology
Total funding: $513,147
Title of research award:
Development of drug-loaded antibody-targeted nanoparticles to kill colorectal cancer cellsDevelopment of
drug-loaded antibody-targeted nanoparticles to kill colorectal cancer cells
Lay Description (from application):
COLORECTAL CANCER (CRC) is the most common cancer in the Western world. In Australia, the fiveyear survival rate after surgical resection of the primary lesion is 55%, and for patients with advanced disease
the five-year survival rate is less than 10%. Colorectal cancer is relatively resistant to radiotherapy and
chemotherapy and therefore there is great emphasis on identifying alternative modes of treatment. One
approach that is attracting considerable attention is IMMUNOTHERAPY. In particular, the A33 ANTIBODY
system appears to have the potential to target colorectal cancer cells and achieve therapeutic outcomes. The
A33 system has been well characterised in both a clinical and laboratory setting over the last few years and
recent clinical trials with humanised versions of the A33 antibody have demonstrated rapid localisation and
accumulation of radiolabelled A33 to colorectal cancer lesions. The application of NANOTECHNOLOGY to
biological systems is likely to transform the way we treat a variety of diseases over the course of the next
decade. Nanosized drug delivery vehicles have the potential to revolutionise the treatment of a number of
diseases, cancer in particular. Hollow capsules can be synthesised with a drug sequestered inside the capsule,
where the capsule wall performs a dual role of protecting the body from potentially harmful side effects of the
drug, as well as protecting the drug from being degraded by the body. We plan to use these nanosized drug
carriers, functionalised with the A33 antibody, to deliver chemotherapy agents directly to the colorectal cancer
cells. We have recently demonstrated that in vitro, nanocapsules functionalised with the A33 antibody
specifically bind to CRC cells, and once bound, the capsules are internalised. In this proposal we will test the
ability of these particles to kill CRC cells in mice harbouring human tumours.
Research achievements (from final report):
, The treatment of metastatic cancer unavailable to surgery relies heavily on systemic chemotherapy. However,
the amount of chemotherapy that can be administered is frequently restricted by toxic side-effects. Because
strategies capable of overcoming this limitation are likely to improve patient outcomes, we have developed
very small hollow capsules (in the sub-micron size range) that can be loaded with large cytotoxic payloads
tailored to an individual malignancy. To direct these capsules specifically to colorectal cancer cells, we have
coated the capsules with an antibody that recognises a protein displayed on the tumour cell surface. Upon
introduction into the circulation, these capsules are expected to "home" to disseminated tumour deposits, bind
to the tumour cell membranes and be internalised by normal cellular processes. Proof-of-principle studies with
cultured colorectal cancer cells have demonstrated the soundness of this approach. Once inside the cell, we
have shown that the capsules release their cytotoxic payload, resulting in tumour cell death. However,
translating our studies into a preclinical animal model has been challenging. In particular, our sub-micron drug
carriers are rapidly removed from the circulation by tissue-resident macrophages in the liver and spleen.
However, if we block macrophage activity by administering chlodronate liposomes to mice three days prior to
injection of capsules, the capsules persist in the circulation for longer and accumulate within implanted subcutaneous human tumours. While the use of liposomes in this experimental setting is useful, current efforts to
increase capsule circulation times are primarily focused on evading macrophage surveillance by changing their
surface properties.
Expected future outcomes:
As a result of ongoing efforts, we fully expect to be able to modify the surfaces of our tiny capsules with "antifouling" chemical substances such as polyethylene glycol (PEG) and thereby generate drug delivery vehicles
that can evade phagocytosis by tissue (liver and spleen) macrophages and persist for much longer times in the
circulation.
NHMRC Research Achievements - SUMMARY
Name of contact:
Assoc Prof Joan K Heath
Email/Phone no. of contact:
joan.heath@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 433614
Start Year: 2007
CIA Name: A/Pr Joan Heath
End Year: 2008
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Genetic Development (incl. Sex Determination)
Total funding: $376,614
Title of research award:
Discovery and analysis of vertebrate intestinal development genes that may play a role in colon
cancerDiscovery and analysis of vertebrate intestinal development genes that may play a role in colon cancer
Lay Description (from application):
Colorectal cancer (CRC) causes more cancer deaths in Australia than any other cancer. While early detection
improves survival rate, nearly half of all CRC patients succumb to the disease within five years. In general,
metastatic CRC is resistant to chemotherapy and radiotherapy and new therapies are required. An increased
knowledge of the processes that contribute to the malignant state is likely to suggest new targets for treatment.
CRC, like all cancer, is the result of genetic abnormalities (mutations) that are acquired over the course of a
lifetime. Together the mutated genes produce changes in cell behaviour in processes such as growth, migration,
angiogenesis (the ability to attract a blood supply) and cell death. All of these processes are active during
normal development of a vertebrate organism, but are generally shutdown in the adult state, except in cancer.
In this study we will analyse a group of genes that we have recently shown to be indispensable for normal
intestinal development in zebrafish. Zebrafish are small tropical fish that are used frequently for genetic
studies. They are very closely related to mammals and it has been shown that the genetic pathways that control
the development of this animal are highly conserved in fish and mammals. Importantly, the genetic pathways
that lead to cancer in humans are also strikingly similar in zebrafish. Our experiments will use mouse models
to discover whether the zebrafish genes we have identified can lead to cancer when they are aberrantly
expressed in the intestines of mice. Any genes that are found to contribute to the development of cancer in
these models could become potential new targets for cancer therapy.
Research achievements (from final report):
During the two year duration of this grant, the Investigators successfully analysed embryos of a model
vertebrate organism, zebrafish, to identify genetic pathways that are crucial for the expansion of the developing
intestine. In this study, the intestine was used as an example of an organ that achieves rapid changes in growth
and differentiation during early development. Tumours exhibit similar behaviours as they grow and spread
throughout the body. We used a "forward genetics" (genetic screen) approach to identify the key genes that
govern the expression of these properties. This involved introducing point mutations into the genome of adult
male zebrafish by exposing them to a chemical (ethylnitrosourea) in their tank water. The introduced mutations
were then propagated into subsequent generations of progeny by in-breeding, allowing the consequences of the
behaviour of the mutated genes to be exhibited. By selecting for mutated offspring that displayed abnormalities
in the shape and size of the intestine, we identified a panel of intestinal mutants for further study. Using a
technique called positional cloning; we subsequently identified 7 genes that are indispensible for normal
intestinal development. Interestingly, these genes play well-characterised roles in multiple complex cellular
functions, such as nuclear pore formation, ribosome biogenesis, gene transcription, alternative splicing of
mRNA and intracellular protein trafficking. In future studies funded by an NHMRC Colon Cancer Program
grant, our efforts will be directed towards inhibiting these processes in mammalian cell culture and animal
model systems to determine whether these genes could provide fruitful targets for killing tumours.
Expected future outcomes:
Our expectations are that at least one of the human orthologues of our cloned zebrafish genes will be
deregulated in human colon cancer and represent a valid target for colon cancer therapy. Our studies will result
in several publications in internationally respected journals.
Name of contact:
Assoc Prof Joan K Heath
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
joan.heath@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 433616
Start Year: 2007
CIA Name: A/Pr Matthias Ernst
End Year: 2008
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Oncology and Carcinogenesis
Total funding: $381,821
Title of research award:
Molecular identification of causative genetic and epigenetic alterations that induce and promote colorectal
cancerMolecular identification of causative genetic and epigenetic alterations that induce and promote
colorectal cancer
Lay Description (from application):
The majority of mouse models currently employed to study colorectal cancer have two failings. The first is that
they tend to focus on small intestinal cancers rather than colorectal cancers. It is important to note that small
intestinal cancers are in the minority of gastrointestinal cancers in humans. The second problem is that the
genetic lesions introduced into mice are mostly in all cells throughout development. This is a poor
representation of the random nature of genetic changes that underpin the probable cause of colon cancer. We
therefore propose to genetically engineer unique mouse models that focus on colon cancer to most closely
replicate the situation in human disease. These models will then be available to others and us to develop and
test therapies to prevent and/or treat colorectal cancer that will ultimately be used in patients.
Research achievements (from final report):
The interaction between the Wnt-APC pathway and c-Myb has been extensively investigated. We suspected
that adenomas in the colon and small intestine would over-express c-Myb and c-Myc, which we have now
confirmed is the case based on more than 40 examples from each organ. We have also shown for the first time
that c-myb gene dosage significantly affects the rate at which APCmin/+ mice need to be sacrificed due to
adenoma burden. Heterozygous c-myb x APCmin/+ mice survive twice as long as APCmin/+ mice on a wild
type background. To advance our sporadic c-myb transgenic model for colon cancer initiation we have
generated 6 transgenic lines that display germline transmission with transgene expressing in the GI tract. We
have also investigated early events in the colons of APCmin/+ mice to address changes in mitosis as crypts
transform into adenomas. Techniques that evaluate mitosis in vivo and by isolating crypts have now been
developed. These approaches will be used to assess other sporadic mutants that we are generating. We have
also extended our analysis of the role of the gp130 Jak/Stat signalling pathway on gastric mucosa and
tumorigenesis. Finally, our growing awareness of early events in colonic crypt transformation have lead to
several related publications in other stem cell tissues such as the neurogenic stem cells and skin
stem/progenitors activated during dermis/epidermis repair.
Expected future outcomes:
Since this project grant was rolled into the NHMRC Colon Cancer Program Grant (487922, awarded to CIA
and CIB and others) after only 2 years running, the original goal/hypothesis not investigated during the first
two years will be pursued in the context of the Program Grant.
Name of contact:
Matthias Ernst
Email/Phone no. of contact:
matthias.ernst@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 433617
Start Year: 2007
CIA Name: A/Pr Matthias Ernst
End Year: 2010
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Oncology and Carcinogenesis
Total funding: $674,142
Title of research award:
Validation of Stat3 as a therapeutic target in diseases arising from its inappropriate activation by gp130
cytokinesValidation of Stat3 as a therapeutic target in diseases arising from its inappropriate activation by
gp130 cytokines
Lay Description (from application):
Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of
several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor
molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to
understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach
lining cells. We will employ a number of strategies to establish molecularly the extent to which this mouse
model is informative for gastric cancer inhuman. In aprticular we will identify the genes that are involved in
the progression of the disease. One important focus of the project is to see whether or not the moelcule (called
Stat3) whose aberrant activation triggers the disease in the mouse could provide a future pharmacological
target for intervention with the disease. Similarly with expertise of CIB, we will investigate with novel
proteomics techniques whther we can identify a protein in the serum of these mice, which could give us aclue
of whether or not the mouse ahs already developed disease. Such a protein could be of potentail diagnostic
importance in the future to screen human for gastric cancer which in its eraly stages is usually without any
clinical symptoms. In a related Aim we will find out the gene that can genetically cooperate with Stat3 and that
is required to enable survival of newborn mice. It may well turn out mOur proposal combines the expertise of
the two investigators in signal transduction and that this gene may be an important determinant to ensure that
Stat3 triggers physiological rather than pathological responses in many differnet organs.
Research achievements (from final report):
We have successfully continued to find remarkable similarities between gene expression patterns between
mouse and human disease. Most importantly however, is our recent finding that the disease in gp130F/F mutant
is indeed dependent on inflammation (as in the case of chronic H.pylori infection-associated intestinal-type
human gastric cancer. This finding further validates these mice as a preclinical model for metaplastic human
gastric model. Our findings that systemic therapeutic inhibition of Stat3 hyperactivation selectively reduces the
burden of existing gastric tumours is of direct relevance to the treatment of the human disease., We have found
remarkable similarities between gene expression patterns between mouse and human disease. Most importantly
however, is our finding that the disease in gp130F/F mutant is indeed dependent on inflammation (as in the
case of chronic H.pylori infection-associated intestinal-type human gastric cancer). This finding further
validates these mice as a preclinical model for metaplastic human gastric cancer. Our findings, that systemic
therapeutic inhibition of Stat3 hyperactivation selectively reduces the burden of existing gastric tumours, are of
direct relevance to the treatment of the human disease. Following the removal of the most highly abundant
serum proteins, a comprehensive comparison between sera from tumour-bearing gp130F/F or gp130F/F;iIL6-/, mice and tumour-free gp130F/F;Stat3+/-, IL6-/- or wild-type mice revealed 29 serum proteins with
consistently altered abundance between the tumour-bearing and tumour-free mice. These 29 proteins are
currently being validated in human samples (NHMRC grant APP1010728) and filing of the corresponding
provisional patent application is under consideration. The research funded by this grant has culminated in the
publication of full-length articles in Cancer Cell (x1), Journal of Clinical Investigations (x1) and Journal of
Immunology (x3) and many other high impact journals.
Expected future outcomes:
The molecular insight gained through this work has resulted in several collaborations with pharamceutival
companies (incl. Eli Lilly, Novartis) and, most importantly, in a collaborative research agreement with CSL
NHMRC Research Achievements - SUMMARY
Ltd for the development of anatgonists that mitagate inflammation dependent on Stat3 activation within the
tumour microenvironment.
Name of contact:
Matthias Ernst
Email/Phone no. of contact:
matthias.ernst@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 433629
Start Year: 2007
CIA Name: Dr Mhairi Maxwell
End Year: 2010
Admin Inst: Ludwig Institute for Cancer Research Grant Type: Early Career Fellowships (Australia)
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $282,008
Title of research award:
Signaling networks: examining interplay between Lyn and SHIP1 in haematopoiesis, tumor suppression and
autoimmunitySignaling networks: examining interplay between Lyn and SHIP1 in haematopoiesis, tumor
suppression and autoimmunity
Lay Description (from application):
Not Available
Research achievements (from final report):
Problems with blood cell development and function can result in autoimmunity and chronic inflammatory
disease, causing significant long-term health issues for many Australians. This study has significantly
expanded our understanding of the immune processes that go wrong in these conditions. A major focus was on
the roles of the enzymes Lyn and SHIP-1, exploring their contributions in promoting susceptibility to
autoimmune and inflammatory disease. These findings may contribute to future development of more effective
therapies for patients with diseases like systemic lupus erythematosus (SLE) and chronic obstructive
pulmonary disease (COPD).
Expected future outcomes:
This project has significantly expanded our understanding of the immune processes that go wrong in
autoimmune disease and inflammatory diseases. The findings will assist in the identification of potential targets
for development of more effective therapies.
Name of contact:
Mhairi Maxwell
Email/Phone no. of contact:
Mhairi.Maxwell@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 487905
Start Year: 2008
CIA Name: Prof Jonathan Cebon
End Year: 2012
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Research Fellowships
Main RFCD: Tumour Immunology
Total funding: $367,153
Title of research award:
Practitioner FellowshipPractitioner Fellowship
Lay Description (from application):
I am a medical oncologist developing immunotherapeutics for the prevention and treatment of cancer.
Research achievements (from final report):
During the tenure of this Fellowship I have combined a career in translational research with clinical practice
and clinical leadership in Oncology at Austin Health. My research activities have focused on malignant
melanoma and the immunotherapy of cancer. This work has been supported by the Fellowship, Ludwig
Institute for Cancer Research and grants for projects (NHMRC, Melanoma Research Alliance) and clinical trial
activities. This has culminated in more than 39 peer reviewed publications since 2008 and 29 conference
abstracts and have been lead investigator on 16 Human research ethics committee approved projects. I have
played an integral part in the successful lobbying of government and donors, resulting in the opening to Olivia
Newton John Cancer & Wellness Centre Sept 2012. I actively contribute to organisations such as: Cancer
Trials Australia, the Victorian Cooperative Oncology Group, the Cancer Vaccine Collaborative, NHMRC,
Melanoma Research Alliance, the Cancer Council of Victoria and the Northern & Eastern Metropolitan
Integrated Cancer Service (NEMICS). In addition to my clinical and research interests, I am actively involved
in training and mentoring of Medical Oncology Advanced Trainees, Clinical Research Fellows, post docs and
postgrad research students.
Expected future outcomes:
As Director of LICR- Melbourne Austin Branch my goal is to transform the cancer research capabilities at the
Austin Health site into a world-class comprehensive program encompassing bench- to-bedside research.
Name of contact:
Jonathan Cebon
Email/Phone no. of contact:
jonathan.cebon@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 489418
Start Year: 2008
CIA Name: A/Pr Lara Lipton
End Year: 2010
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Oncology and Carcinogenesis
Total funding: $620,198
Title of research award:
Analysis of gene amplification-loss and methylation associated with progression to metastatic colorectal
cancerAnalysis of gene amplification-loss and methylation associated with progression to metastatic colorectal
cancer
Lay Description (from application):
Many bowel cancers can be removed by surgery, but in many cases the cancer reoccurs. While chemotherapy
can reduce the chance of recurrence, it can produce significant side effects. Currently there are few markers to
indicate change of recurrence, therefore deciding who should, or should not receive chemotherapy is difficult
to decide. This study will analyse differences in DNA from patients that do and do not relapse, to guide future
decisions on patients who will benefit from chemotherapy.
Research achievements (from final report):
This project grant has enabled establishment of a multi-institution collaboration involving the Ludwig Institute
for Cancer Research, CSIRO Preventative Health Flagship and Prince of Wales Clinical School. Jointly, this
consortium has collected and analysed colorectal cancers from 80 stage C patients who have not recurred for
three years, and primary cancers and metastases for 80 patients who have recurred. Cancer and matched normal
samples have been analysed using SNP arrays, and all cancer samples have been analysed for mutations in
twelve cancer genes, microsatellite instability and selected methylation markers. A computational analysis
algorithm, OncoSNP, has been developed in collaboration with researchers from the University of Oxford for
accurate detection of somatic DNA copy number aberrations and loss of heterozygosity from the SNP array
data (Genome Biology, 2010). We have fine-mapped multiple minimal regions of chromosomal gain and loss
associated with disease prognosis, and current sequencing studies are focusing on identifying the underlying
target genes. Similarly, outcome-associated germline variants have been identified which will be followed up
in a new NHMRC project grant received in 2011. Tumour ploidy status inferred from these data has been
investigated as a prognostic indicator. This grant has further enabled major technology development for the
analysis of genome-wide methylation patterns which is currently being applied to all cancer samples. Our
methodology is suitable for both microarray and high throughput sequencing analysis.
Expected future outcomes:
Genome-wide DNA methylation and copy-number data will be integrated with mutation data to define an
optimal predictor of patient outcome (relapse) and progression to metastasis.
Name of contact:
Dr Oliver Sieber
Email/Phone no. of contact:
oliver.sieber@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 542508
Start Year: 2009
CIA Name: Prof Weisan Chen
End Year: 2011
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Cellular Immunology
Total funding: $480,127
Title of research award:
Discovery of long CD8+ T cell epitopes uncovers a hidden reservoir of immunodominant, anti-tumour
responsesDiscovery of long CD8+ T cell epitopes uncovers a hidden reservoir of immunodominant, antitumour responses
Lay Description (from application):
Stimulating killer T cells to eliminate tumours has been one of the ultimate yet elusive goals of cancer vaccine
development. Vaccines aimed at stimulating killer T cells are similar to those generated under natural
conditions. However, special strategies are needed to vaccinate beneficial killer T cells that are not normally
part of the natural immunity. In this project, we will explore such a scenario and dissect the related mechanisms
contributing to such differential immune outcomes.
Research achievements (from final report):
Dendritic cells (DCs) are responsible for initiating cellular immunity by displaying tumour antigen fragments
(also called epitopes). However, DCs have been reported to possess different antigen degradation machinery as
that in the tumour cells. Therefore, it is possible that the epitopes displayed by tumour cells and DCs could be
partially mismatched. To fully explore such differential epitope display, we have studied in detail two CD8+ T
cell epitopes derived from tumour antigen NY-ESO-1, i.e. 60-72 and 88-96. We found that the display of the
two epitopes by tumour cells and DCs are quite different and contrasting. We also found the formulating the
NY-ESO-1 into an adjuvant call ISCOMATRIX greatly helped its immunogenicity and significantly enhanced
its epitope display on DCs. These results actually explained our observations from melanoma clinical trial
patients very well, indicating a significant translational value of our studies. The above work are either
published or submitted., As the epitope 60-72 is unusually long yet recognised by many different T cells, an
opposite observation to what has been published so far. We also wanted to elucidate the potential underlying
structure basis for such an observation. We have now made multiple functional, reconbinant TCR and HLA
molecules complexed with this long peptide. We are in the process of getting crystals for these molecular
complexes. The structures will provide important insights into how long epitopes are selected and how TCRs
interact with long peptide complexed to the HLA molecules.
Expected future outcomes:
Three publications are expected:, 1.
Polyclonal T-cell Receptors
Recognise an Unusually Long Tumour Antigenic Peptide Complexed to HLA-B7, 2.
Analysis of T
cell response to a 13 Amino Acid Tumour Antigenic Peptide in HLA-B7 Transgenic Mice with or without
Immunoproteasome Deficiency, 3.
Identification of an unusually long
epitope from the tumor antigen NY-ESO-1 which is naturally presented on HLA-B7
Name of contact:
Weisan Chen
Email/Phone no. of contact:
weisan.chen@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 542510
Start Year: 2009
CIA Name: Prof Jonathan Cebon
End Year: 2011
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Tumour Immunology
Total funding: $526,878
Title of research award:
Immune targeting of melanoma stem cellsImmune targeting of melanoma stem cells
Lay Description (from application):
Cancers have been found to contain 'stem cells' which are responsible for tumours growing and spreading
throughout the body. Cancer therapies often target the cancer, but it is now clear the these treatments will only
be effective if they can eradicate the malignant stem cells. This research investigates the best way of 'targeting'
cancer stem cells in malignant melanoma as a means of developing more effective anti-cancer treatments.
Research achievements (from final report):
Stem cells have the capacity to self-renew, repopulate and migrate. We identified behaviour in melanoma that
was similar to these properties of stem cells, and this grant sought to determine whether stem cells might exist
and explain some of the malignant characteristics of melaoma. Further investigation of these cells showed that
stem-like cells can indeed arise within tumours, although they are not a stable cell poulation; rather they can
arise within the tumour as transient changeable cell populations. Nonetheless the emergence of such cells
probably contributes to cancer progression. We therefore focussed on identifying molecules that regulate this
changeability and found a group of molecules that can serve as targets for therapy and for immune recognition.
This gives rise to new potential therapies to block the spread and progressin of melanoma in humans.
Expected future outcomes:
It is expected that new targets can be identified to inhibit the progression and spread of malignant melanoma
and stop or delay the failure of anti-cancer drugs
Name of contact:
Prof Jonathan Cebon
Email/Phone no. of contact:
jonathan.cebon@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 542512
Start Year: 2009
CIA Name: Prof Andrew Scott
End Year: 2011
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Tumour Immunology
Total funding: $566,087
Title of research award:
Regulatory mechanisms of antibody cytotoxicity for cancer therapyRegulatory mechanisms of antibody
cytotoxicity for cancer therapy
Lay Description (from application):
Use of antibodies for cancer therapy, where a protein is made in the laboratory to recognize and act on cancer
cells that have a target antigen, has emerged as an important therapeutic area in oncology. The lewis-y (Ley)
antigen is found in over 70% of epithelial cancers. We have developed an antibody against Ley (hu3S193)
which can target cancer cells. Our research is aimed at developing optimal cancer cell killing by our anti-Ley
antibody.
Research achievements (from final report):
, This project has explored the interactions between a novel recombinant antibody (hu3S193) against the Ley
antigen expressed in most epithelial cancers, and immune regulatory factors responsible for modulating the
immune effector function of human IgG. Through this research, recombinant antibody forms against the Ley
antigen have been created with improved anti-cancer properties both via indirect mechanisms such as enhanced
delivery of radioactivity to the tumour, or via direct mechanisms such as enhanced tumour cell killing activity
via enhanced engagement of the immune system. Structural analysis of the different antibody forms has given
insight into the small structural changes necessary to obtain these altered properties of antibodies. Structural
analysis has also helped identifying key residues in the Fc fragment of IgG antibodies responsible for the
interaction with the neonatal receptor FcRn, C1q and FcgR.
Expected future outcomes:
It is our intention to develop a new class of hu3S193 that would be produced and taken into the clinic for
therapeutic studies in cancer patients. Our findings would also be readily translated to other antibodies used in
the clinic, with the aim to improving clinical outcomes for patients treated with antibody-based therapies.
Name of contact:
Professor Andrew Scott
Email/Phone no. of contact:
andrew.scott@ludwig.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 542531
Start Year: 2009
CIA Name: Prof Antony Burgess
End Year: 2012
Admin Inst: Ludwig Institute for Cancer Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $550,725
Title of research award:
Wnt signalling in colon cancerWnt signalling in colon cancer
Lay Description (from application):
Colorectal cancer is a common malignancy in Australia and the mutation of one gene (Apc) is implicated in
>80% of the cases. We aim to understand Apc biochemistry in normal and colon cancer cells by integrating
mathematics with our experimental biology program. The main outcomes for this project will be a better
understanding of the regulatory systems perturbed in colon cancer. We believe that the insights gained by our
research will point the way to more effective treatments of colon cancer.
Research achievements (from final report):
Our research obtained quantitative data on the proteins which change when cells are stimulated by a
morphogenic factor (wnt). Colon cancer cells are overly sensitive to this stimulation. Our studies aimed to
identify the differences in these colon cells which were responsible for the over reaction and consequential
accumulation of β-catenin in the cytoplasm of colon cancer cells. Our kinetic data shows that there is little
change in either the rate of synthesis or the rate of degradation of β-catenin in mammalian cells after
stimulation by wnt. However, β-catenin, was discovered to migrate from the membrane to the cytoplasm after
wnt stimulation. Our data was used to parameterize a computer simulation of the responses of normal and
cancerous colon cells to wnt stimulation. Our computer program predicted the interactions between two
regulatory proteins axin and apc and the cell adhesion system involving β-catenin and E-cadherin. We are
aiming to predict the effects of wnt on both cell adhesion and β-catenin regulated gene transcription. Our initial
experiments indicated that a significantly different model is required for understanding the distribution and
action of β-catenin isoforms. Our studies indicated a more significant tole for apc at the peripherary of the cell.
Expected future outcomes:
We will progress our measurements of wnt signalling proteins in the cells of normal and cancerous colonic
crypts. We will use this information to parameterize a model to predict the cellular dynamics and interactions
in the crypts; with a view to understanding how the truncation of apc leads to cancer.,
Name of contact:
Professor Antony Burgess
Email/Phone no. of contact:
tburgess@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 191805
Start Year: 2002
CIA Name: Prof Eric Gowans
End Year: 2004
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Medical Virology
Total funding: $452,310
Grant Type:
Title of research award:
The in vitro culture of hepatitis C virus and approaches to the control of replicationThe in vitro culture of
hepatitis C virus and approaches to the control of replication
Lay Description (from application):
HCV is a major cause of liver disease and around 200 million people are currently infected worldwide,
including 200,000 Australians. HCV differs to other flaviviruses. Most notably, around 80% of individuals
develop a persistent infection, accounting for the large number of carriers. This infection is probably life-long
and 40-50% of carriers will develop serious liver disease, including liver cancer. HCV is currently the leading
single indicator for liver transplantation in the western world. These carriers can also transmit the virus to
uninfected individuals. Screening in the blood banks has reduced transmission after blood transfusion to
virtually zero. However, although individuals who share contaminated needles represent a major high risk
population, around 30% of carriers have no acknowledged transmission risk factors, and transmission to
patients in hospitals has been recognised. As a result, it is clear that members of the general population may
still become infected. It has been estimated that there are 10,000 new cases each year in Australia. The best
available treatment is a combination of interferon-alpha and ribavirin, but this is only successful in 40-50% of
carriers. Moreover, many patients fail to tolerate these drugs and the cost restricts treatment to a small
proportion of carriers. As a result,only approx 6,500 carriers have been treated in Australia. A huge backlog in
the liver clinics and the resistant nature of the virus in 50% of patients in Australia mean that these patients will
not be treated unless new therapies are developed. The most effective means to prevent virus infections is by
vaccination. Thus the development of novel antivirals and a vaccine for HCV are priorities. Since the cost of a
single liver transplant is $100,000 the development of such agents is likely to be cost effective. However, it is
necessary to develop suitable cell culture systems to test putative antiviral agents.
Research achievements (from final report):
The aim was to synthesise HCV and to examine potential inhibitors of HCV replication. We examined the role
of the core protein in the inhibition of HCV IRES-directed translation. The core protein inhibited cap- and
IRES- directed translation, although it was 5-fold more specific for the IRES. A synthetic peptide representing
amino acids 1-20 of the core protein duplicated this effect and bound to the IRES as shown by an
electrophoresis. The HCV core protein, expressed from a recVV inhibited cap-and IRES-dependent translation
in CV-1 and HuH7 cells, but was specific for the HCV IRES in HepG2 cells. In contrast, the HBV core protein
(also recognised for its RNA-binding activity) was unable to inhibit either cap- or IRES-dependent translation
in both cell lines. A core protein deleted of amino acids 1-20 was unable to inhibit translation, and a synthetic
peptide representing these amino acids inhibited cellular transcription and HCV transcription 2-fold and 5-fold
respectively in cell lines., We extended our vitamin B12 studies to investigate the HCV IRES domain IV in
translation. Two chimeric elements were constructed to contain the reciprocal domain IV in the otherwise HCV
and CSFV (classical swine fever virus) IRES elements. A specific inhibitor of the HCV IRES, vitamin B12
inhibited translation, directed by all IRES elements which contained the HCV IRES domain IV and the GBV-B
IRES (the only member of the Hepacivirus genus in the Flaviviridae that contains a domain IV similar in
structure to that of HCV) and is the only other member of the genus that specifically targets hepatocytes. In
contrast, the HCV core protein only inhibited translation from the wild type HCV IRES. Thus, the mechanism
of inhibition by core and vitamin B12 differ because different regions of the IRES are targeted.
Expected future outcomes:
We will examine the potential of the peptide-mediated inhibition of HCV replication by synthesising a cyclical
peptide and examining the effect of this after delivery to cells which support the replication of HCV RNA. If
NHMRC Research Achievements - SUMMARY
the replication of the virus RNA is inhibited, this will be followed up by toxicity trials. We also plan to
examine the potential of the recBV as a vacine delivery vehicle
Name of contact:
Eric Gowans
Email/Phone no. of contact:
gowans@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 266818
Start Year: 2004
CIA Name: Prof Geoffrey Pietersz
End Year: 2006
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Cellular Immunology
Total funding: $284,250
Grant Type:
Title of research award:
Aldehyde-modified Antigens for the Immunotherapy of adenocarcinomasAldehyde-modified Antigens for the
Immunotherapy of adenocarcinomas
Lay Description (from application):
The incidence of breast cancer in women is 1 in 8 and the frequency of other cancers are rising. Even with
conventional approaches such as surgery, cytotoxic therapy, radiotherapy and combination therapy only a few
cancers are treatable. The development of a cancer vaccine will greatly benefit humanity similar to childhood
and adult vaccinations for preventing infectious disease. In this proposal we intend to chemically modify a
synthetic protein called mucin 1 (MUC1) which is exprssed on cells in breast cancer to make it more
immunogenic - that is make it look more like a foreign protein so that the immune cells can make antibodies or
killer cells that recognise it. These activated cells can now migrate to the tumour sites and kill the invading
tumour. In order to do this we are going to introduce mannose, a particular sugar that can bind to important
white blood cells and an aldehyde group that can activate immune cells. We will test the effectiveness of the
modified proteins in mice to see if they can generate an good immune. If this is satisfactory then we will see if
mice are vaccinated with these modified proteins can reject implanted mouse or human tumours. If these
experiments are successful further work can be done with human cells and later clinical trials. Any methods
developed here will be applicable to other cancers and also infectious diseases.
Research achievements (from final report):
We have utilised chemical methods to modify proteins so that they can be readily identified by immune cells
and generate an immune reponse. These activated killer cells are now primed to kill cancer cells that express
this protein that may occur in the body. We have used a model antigen and a breast cancer associated antigen
known as mucin 1 (MUC1). In the preclinical studies in mice we demonstrated that when mice are immunised
with the modified protein they are protected from a challenge with tumour cells. This is particularly relevant as
this method can be used to modify a protein from any source be it tumour, bacteria or viruses and therefore the
possibility of vaccinating against diseases caused by these organisms. Future work with human cells could
possibly lead to clinical trials. When safety has been established in patients with cancer eventually this vaccine
may be given to paties at risk of getting cancer.
Expected future outcomes:
With further development work this research may translate to a cancer vaccine. The strategy is also applicable
to vaccines for infectious diseses.
Name of contact:
Prof Geoffrey A Pietersz
Email/Phone no. of contact:
g.pietersz@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 331305
Start Year: 2005
CIA Name: A/Pr Monica Slavin
End Year: 2008
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Infectious Diseases
Total funding: $1,095,500
Grant Type:
Title of research award:
The clinical value of serology and molecular tests for diagnosing Invasive Aspergillosis in at-risk hematology
patientsThe clinical value of serology and molecular tests for diagnosing Invasive Aspergillosis in at-risk
hematology patients
Lay Description (from application):
Aspergillus is a fungus found in soil, on farms and on construction sites. In those whose immune system is
impaired it causes severe infection. The people who are particularly at high-risk of Aspergillus infection (called
Invasive Aspergillosis) are those with acute leukaemia on chemotherapy or post bone marrow transplantation.
Currently 15% of those at high-risk get Invasive Aspergillosis and 58-93% of those infected die. The main
reason for this high death rate is that our current diagnostic tests are not good at detecting infection or often
only detect the infection at advanced stages when treatment is ineffective. Because of the limitations of current
diagnostic tests the current practice is to give empiric antifungal therapy (EAFT) early to treat Invasive
Aspergillosis. However studies have demonstrated that this therapy has only resulted in a minor reduction in
the mortality rates and it causes significant drug toxicity. It is a suboptimal treatment modality. New tests have
been developed to diagnose Invasive Aspergillosis. These tests are for the detection of an Aspergillus protein in
blood and for the detection of Aspergillus DNA in the blood. Available data suggests that these new tests are
sensitive in the detection of Invasive Aspergillosis. Also other studies suggest that these new tests make an
early diagnosis and seem to be able to monitor responses to treatment. However no study has been performed
to date which demonstrates that the use of these tests can impact on important patient outcomes. This trial is
designed to determine whether the use of the new tests to guide therapy will help improve treatment of Invasive
Aspergillosis, reduce drug toxicity and reduce the death rate in the high-risk patients as compared with the
current standard method of diagnosis and treatment with EAFT. If the trial is successful then this represents a
significant advancement in the treatment and survival of leukaemic and bone marrow transplantation patients.
Research achievements (from final report):
We have conducted the first randomised trial comparing the value of surveillance with the new diagnostic tests
for Invasive aspergillosis (IA) compared to the standard of treatment (empiric antifungal therapy).IA is a major
cause of mortality after intensive chemotherapy or stem cell transplant. It has not been possible to assess
previously whether taking a surveillance and early treatment approach is as good as or better than our current
approach of giving all patients who might have IA antifungal drugs based on non specific signs and symptoms.
These drugs are expensive and have side effects. It may be safe and cost effective to withold these drugs if
patients are monitored with the new diagnostic tests for IA (PCR and galactomannan antigen in blood)., We
have: 1. defined how to use these tests in guiding treatment for IA , 2. standardised testing between Australian
laboratories and optimised testing to give best performance, 3. participated in an international standardisation
of PCR initiative (co-ordinated through the European Union) , 4. Competed the first randomised comparison of
the standard approach to treating IA versus the new approach incorporating these new tests, these tests have the
ability to diagnose IA earlier and to reduce the number of deaths due to IA whilst sparing many patients
unnecessary and toxic treatment
Expected future outcomes:
We can determine whether it is better to use empiric antifungal therapy with its attendant toxicity and cost or
surveillance for IA with new diagnostic tests. Patients undergoing chemotherapy for acute leukemia or bone
marrow transplant may be able to avoid these costly and toxic drugs
Name of contact:
Monica Slavin
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
monica.slavin@optusnet.com.au
NHMRC Research Achievements - SUMMARY
Grant ID: 331309
Start Year: 2005
CIA Name: Prof Peter Gage
End Year: 2007
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Medical Virology
Total funding: $480,750
Grant Type:
Title of research award:
Studies of hepacivirus morphogenesis.Studies of hepacivirus morphogenesis.
Lay Description (from application):
Hepatitis C virus is a major medical problem in Australia and many other parts of the world. The viruses
causes a persistent infection in most infected individuals that results in serious liver disease and liver cancer in
a proportion of patients. Treatment is only possible for a small percentage of patients and many patients are
infected with viruses which are resistant to the best contemporary treatment regimens. The aim of this project
is to develop systems which will result in the assembly of virus particles which can be used to examine the
efficacy of potential antiviral agents, either in the test tube or by infecting an animal model. In particular, we
will examine the contribution of a small viral protein, p7, on virus assembly and secretion from the infected
cell. Recent data suggests that p7 can function to help release virus from the infected cell and a number of
inhibitors of p7 function have been described. We will then use the systems which we develop to determine if
these inhibitors can inhibit virus replication in the test tube and in animal models.
Research achievements (from final report):
We demonstrated that the GBV-B p13 protein has ion channel activity, analogous to the HCV p7 protein.
Amantadine inhibited the ion channel function of the p13 peptide whereas replication of GBV-B in cell culture
was not affected. We also examined the effect of other putative ion channel inhibitors on GBV-B replication
and identified at least two compounds with antiviral activity. We also constructed a chimeric GBV-B in which
the p13 ion channel gene was substituted by the p7 gene from HCV. Direct intrahepatic injection of RNA
derived from this chimeric cDNA clone resulted in a viremia in the marmosets, but this was very transient
(~1week. Nevertheless, it is possible to use this virus to examine the effect of potential inhibitors of the HCV
p7 ion channel. Another chimeric virus was constructed in which the HVR1 region from the HCV E2 protein
was inserted into the E2 protein of GBV-B. This virus also produced a transient viraemia in marmosets. , We
produced several chimeras based on the JFH1 genotype 2a strain and showed that the genotype 1b p7 gene can
substitute for the homologous gene. This has important ramifications for the discovery of novel anti-viral
agents directed against genotype 1 viruses. We also showed that the p7 protein is localised in the endoplasmic
reticulum of infected cells, and that the p7 protein has a function in HCV morphogenesis. We showed that
expression of the p7 protein is vital for HCV synthesis in cell culture experiments, and confirmed the previous
in vivo data.
Expected future outcomes:
We will explore the relationship between p7 and other HCV proteins in the virus replication strategy, examine
possible inhibitors of HCV replication and use our chimeric viruses to examine the effect of inhibitors in
different HCV strains.
Name of contact:
Eric J Gowans
Email/Phone no. of contact:
gowans@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 406651
Start Year: 2006
CIA Name: Prof Steve Gerondakis
End Year: 2008
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $500,945
Grant Type:
Title of research award:
Determining the role of Rel/NF-kB Transcription Factors in Myeloid DifferentiationDetermining the role of
Rel/NF-kB Transcription Factors in Myeloid Differentiation
Lay Description (from application):
Different types of mature blood cells arise from stem cells in a process involving changes in gene expression
that dictate which types of blood cells ultimately develop. A family of gene regulatory proteins called NF-kB
transcription factors has been found to control the pattern of gene expression in a particular blood cell
precursor called a granulocyte macrophage precursor (GMP) that normally generates two types of mature blood
cells called macrophages and neutrophils. In the absence of NF-kB proteins, a change in the pattern of gene
expression in GMPs leads to an imbalance in production of these two blood cell types that now favours the
generation of neutrophils. This work will provide insight into the molecular mechanisms of blood cell
development regulated by NF-kB. With disturbances in the balance of blood cell formation representing a
hallmark of leukemia, understanding how this process is normally controlled may have important implications
for developing therapeutic strategies to combat various types of leukemias.
Research achievements (from final report):
The research undertaken in this grant was directed at understanding how NF-kB gene regulatory factors
controlled the differentiation of blood cell progenitors to develop into either monocyte or neutrophil lineage
cells. Our work has shown that the RelA member of the NF-kB gene regulatory family determines the rate of
transition from a CMP (common myeloid progenitor) to a GMP (granulocyte macrophage progenitor) by
controlling the expression of other crucial gene regulatory factors involved in this process, as well as dictating
GMP to monocyte differentiation in response to specific differentiation factors. Furthermore RelA and another
NF-kB family member c-Rel together regulate gene expression in GMP that is essential for the development of
monocytes in response to a wide variety of differentiation siganls. This work, which identifies a new and
important role for the NF-kB signalling pathway in myeloid cell development will have a signficant imapct on
our understanding of how deregulation of the NF-kB pathway contributes to the development of myelogenous
leukemias, thereby offering up novel avenues for the development of new therapeutic strategies to treat this
form of cancer.
Expected future outcomes:
Future work will determine the precise contribution different NF-kB target genes make to myeloid
development and how provide a better mechanistic insight into how deregulated NF-kB function promotes
myelogenous cancers.
Name of contact:
Professor Steve Gerondakis
Email/Phone no. of contact:
gerondakis@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 433914
Start Year: 2007
CIA Name: Dr Elizabeth Grgacic
End Year: 2009
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Medical Virology
Total funding: $288,210
Grant Type:
Title of research award:
A new insight into hepatitis B infection:the HBV fusion peptideA new insight into hepatitis B infection:the
HBV fusion peptide
Lay Description (from application):
Three hundred and fifty million people worldwide and 250,000 in Australia are chronically infected with
hepatitis B virus (HBV). Without intervention, one third will die as a direct result of this infection through
cirrhosis, liver failure and liver cancer, but current therapies are inadequate. New antiviral treatments requiring
the identification of new antiviral targets are needed to combat the disease but a major obstacle to the study of
HBV is the lack of a cell culture system. As a result nothing is known about how HBV enter and fuses with the
host liver cell but we have made significant progress with the identification of the entry and fusion events of
the related duck hepatitis B virus, using the duck infection model. This knowledge is now ready for application
to the medically important HBV by use of primary human liver cells and the techniques developed in the duck
hepatitis B virus model.
Research achievements (from final report):
Analysis of the role of enzymes in the entry of hepatitis B virus into liver cells suggested that cathepsin L , an
enzyme common to the endosomes in cells and the predicted entry route for HBV, maybe involved. While this
preliminary finding would need to be confirmed in primary human liver cells, it provides some scope for
further studies on the potential use of enzyme inhibitors as therapeutic agents in HBV infection.
Expected future outcomes:
N/A
Name of contact:
Elizabeth Grgacic
Email/Phone no. of contact:
grgacic@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 488405
Start Year: 2008
CIA Name: Prof Mark Hogarth
End Year: 2010
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Humoral Immunology and Immunochemistry
Total funding: $772,315
Grant Type:
Title of research award:
Structure and Function of Receptors for IgG (FcgammaR)Structure and Function of Receptors for IgG
(FcgammaR)
Lay Description (from application):
We are investigating one of the most important receptor families of inflammatory white blood cells - so called
Fc receptors. These are critically important in resistance to infection. Unfortunately they are also crucial in
tissue destruction in autoimmune diseases such as rheumatoid arthritis. We will determine how these receptors
trigger inflammation and use this information for the development of new drugs to treat rheumatoid arthritis
and lupus.
Research achievements (from final report):
We have discovered how antibodies bind and activate inflammatory white blood cells to cause inflammation.
Normally a controlled inflammatory response by antibodies protects against infection and is the basis of all
successful vaccines. Furthermore many modern cancer therapies using genetically engineered monoclonal
antibodies depend on this inflammation to eliminate cancers. By contrast in autoimmune diseases such as
rheumatoid arthritis and lupus the inflammation or antiphospholipd syndrome is uncontrolled and leads to
severe tissue destruction and severe life threatening illness. Our discoveries show how antibodies bind to cellsurface receptors called Fc receptors and switch on inflammatory cells. As a result we can develop strategies to
prevent antibody interaction with receptor and thereby prevent inflammation. Indeed we have successfully
tested a range of potential new compounds that it prevent inflammation in animal models. Furthermore we
have also found genetic differences in the Fc receptors lead to different levels of inflammatory cell activation
and are associated with a number of life-threatening complications of diseases such as lupus. A further
application of our discovery is its use in the development and improvement of new selective antibody-based
treatments for cancer. New so-called biological therapies used genetically engineered monoclonal antibodies
which target cancer cells and eliminate these by activating inflammatory cells through their Fc receptors.
Manipulating the activation of the Fc receptors will lead to improved monoclonal antibody therapeutics. This
pioneering work may lead to the development of new treatments for several intractable human diseases.
Expected future outcomes:
Broader understanding of how Fc receptors activate inflammatory leucocytes in inflammatory disease and in
normal immune responses.New anti-inflammatory therapeutics that prevent immune complex activation of
with Fc receptors; therapeutics include small chemical entities and biological "blockers".Improved cancer
antibody therapeutics.Further development of Australian intellectual property.
Name of contact:
P.Mark Hogarth
Email/Phone no. of contact:
pmhogarth@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 488408
Start Year: 2008
CIA Name: Prof Geoffrey Pietersz
End Year: 2010
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Cellular Immunology
Total funding: $540,075
Grant Type:
Title of research award:
Polynucleotide Vaccine Based On Targeted Delivery To Antigen Presenting CellsPolynucleotide Vaccine
Based On Targeted Delivery To Antigen Presenting Cells
Lay Description (from application):
We have previously generated a vaccine for breast and other adenocarcinomas by linking a breast cancer
associated protein, MUC-1, to a sugar called mannan. This complex was capable of eradicating tumours in
mice and its efficacy has been evaluated in human clinical trials (12 in total). As an extension to these studies
we have now found that this sugar, mannan, can be used to deliver DNA to immune cells. The current project
will evaluate a DNA vaccine for breast cancer.
Research achievements (from final report):
The major acheivement in this project is the demontration that genetic material encoding for proteins
associated with cancer cells (Mucin 1 or Telomerase) can be delivered to antigen presenting cells known as
dendritic cells (DC) using the sugar mannan obtained from Bakers's yeast. The genetic material delivered by
mannan to DC is processed and presented to naïve T cells which are then activated and demonstrate specificity
to the cancer cells which express the protein. When we used genetic material encoding the model protein
chicken egg albumin or a cancer protein known as mucin 1 (MUC1), killer T cells were generated that can
recognise and kill cancer cells in culture. We then showed that the mice immunised with the mannan-linked
genetic material were protected from a lethal dose of the tumour ., The potential benefit and significance of this
work is discovering a novel strategy to deliver genetic material for vaccines or gene therapy. DNA vaccines are
highly desirable since it is easy to prepare and generate large amounts of pure genetic material (DNA plasmids)
and these are not infectious and safe to use in humans than viral delivery methods for DNA.
Expected future outcomes:
The future outcomes would be to deliver small polynucleotides that can inhibit the expression of various
proteins. This strategy will use the mannan based delivery to turn off proteins that will result in turning off
tumour promotion or enhancing the function of dendritic cells.
Name of contact:
Geoffrey A Pietersz
Email/Phone no. of contact:
gpietersz@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 543325
Start Year: 2009
CIA Name: Prof Geoffrey Pietersz
End Year: 2009
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Development Grants
Main RFCD: Cellular Immunology
Total funding: $178,400
Grant Type:
Title of research award:
Novel vaccine formulation for immunotherapy of adenocarcinomasNovel vaccine formulation for
immunotherapy of adenocarcinomas
Lay Description (from application):
We have designed a vaccine based on a unique delivery system. Mice immunised with vaccine were protected
from a tumour challenge. We will now design a vaccine with a cancer associated protein so that people once
immunised can make killer cells. Since humans have different genetic makeup we will produce a vaccine
which is more effective and will benefit everyone. This vaccine will be more effective than a current vaccine in
that has yielded promising results in humans.
Research achievements (from final report):
A vaccine for cancer is the holy grail for cancer therapy. Vaccines have eradicated deadly diseases like small
pox and constantly protects us from flu and tetanus and small children from deadly infectious diseases. For
cancer, vaccines have been less than sucessful. We currently have a vaccine in clinical trial using protein called
mucin1 (MUC1) linked to a complex sugar (MFP) but effective in only 50% of the population and it is
heterogenous. In this project we produced a different MUC1 protein that will be effective in more women. We
also designed a new way of attaching the sugar to the mucin1. This new strategy involved using a tree like
structure with a number of sugars to make a complex sugar that we linked to MUC1.We were able to show that
the new vaccine was working in mice because the mouse made immune respones to it of the right type. We
showed that the new vaccine construct was more effective than the MFP.
Expected future outcomes:
We hope that this novel strategy can be further developed by validating it on human cells.
Name of contact:
Geoffrey A Pietersz
Email/Phone no. of contact:
gpietersz@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 603713
Start Year: 2010
CIA Name: Dr Raffi Gugasyan
End Year: 2012
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Cellular Immunology
Total funding: $438,040
Grant Type:
Title of research award:
NFkB1 is a novel regulator of CD8+ T cell development and memory cell generationNFkB1 is a novel
regulator of CD8+ T cell development and memory cell generation
Lay Description (from application):
This project is focused on understanding the role of a regulatory protein- NFkB1 and how it is capable of
controlling the development of a class of white blood cells termed T cells. Using a mouse model, we reveal
how the absence of NFkB1 is important for producing memory T cells. Studies are proposed to determine
whether this is an novel way for generating long lived memory T cells against viral infections and cancer, and
potentially a new strategy for vaccine development.
Research achievements (from final report):
An important goal of vaccine development is to enhance the formation of long-lived memory T cells. The
major benefit of memory cells for humans is their ability to rapidly combat invading pathogens that follows a
previous encounter with the same pathogen. A vaccine for measles displays the classic hall mark of a memory
response - vaccination of infants who are yet to establish a fully competent immune system are protected
against subsequent challenge by the highly infectious virus that is responsible for promoting measles. Our
research for novel vaccines against existing pathogens is ongoing, but new pathogens such as "swine flu (H1N1
virus) are also being recognised. Thus, the need to develop novel strategies to enhance immune function and
memory is paramount.In this study, Gugasyan and colleagues have identified a regulatory protein called
NFkB1, that has a striking effect on the development and function of CD8 T cells - a subset of T lymphocytes
(white blood cells) known to provide protective immunity against numerous viral infections and play a vital
role in anti-tumour immunity. Intriguingly, CD8 T cells that develop in a mouse model that lacks the gene for
NFkB1 acquire the properties of memory cells. That is, these T cells display markers associated with memory
and when challenged they function rapidly like memory cells to counter the challenge. Further research will be
required to understand how these cells are produced.
Expected future outcomes:
The unique aspect of NFkB1-deficient CD8 T cells is their ability to function like memory cells without prior
exposure to pathogenic challenge. Potentially, this may provide a rapid first line of defence against invading
pathogens in newborn and infants that lack a fully efficient immune system.
Name of contact:
Dr Raffi Gugasyan
Email/Phone no. of contact:
gugasyan@burnet..edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 434227
CIA Name: A/Pr Mark Molloy
Admin Inst: Macquarie University
Main RFCD: Medical Bacteriology
Total funding: $471,059
Start Year: 2007
End Year: 2012
Grant Type: Career Development Fellowships
Title of research award:
Protein biomarkers for translational colorectal cancer researchProtein biomarkers for translational colorectal
cancer research
Lay Description (from application):
Not Available
Research achievements (from final report):
New methods were developed using mass spectrometry to measure the amount of specific proteins that could
act as biomarkers in patient blood samples and resected tumour specimens from colorectal cancer patients. Our
guidance on the development of this technique has been widely acknowledged in the protein-research
community. The research led to the identification of several new prognostic biomarker proteins and other
proteins that may predict response of cancer patients to chemotherapy drugs. Tthe prognostic biomarker
findings were validated in large patient cohorts to give strong statistical confidence to the data. We also
characterised protein expression profiles amongst a range of different stage colorectal tumours to gain more
insight into the molecular mechanisms that drive these tumours. Ultimately, we expect that this research will
help to personalise the treatment of colorectal cancer patients based on individual patients molecular
phenotypes. Patients will be dichotomised for chemotherapy drug selection and this will lead to less toxicity,
more efficient uses of hospital resources, improved economic outcomes per patient treatment and overall better
survival outcomes for cancer patients.
Expected future outcomes:
Measurement of protein biomarkers will be routinely incorporated into cancer patient management plans to
help clinicians select the optimum treatment approach for individuals guided by their molecular phenotype.
Name of contact:
Mark Molloy
Email/Phone no. of contact:
mark.molloy@mq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490037
CIA Name: Prof Simon Foote
Admin Inst: Macquarie University
Main RFCD: Genetics not elsewhere classified
Total funding: $8,752,567
Start Year: 2008
End Year: 2013
Grant Type: Programs
Title of research award:
Genetic and Bioinformatic Analysis of Complex Human DiseasesGenetic and Bioinformatic Analysis of
Complex Human Diseases
Lay Description (from application):
Some human diseases are common in families; examples include prostate cancer, blood cancers, epilepsy and
diabetes. Therefore, close relatives of individuals with a disease have an increased risk of being affected by this
disease, implying a genetic basis. Finding the cause of these diseases is difficult, we will be developing novel
approaches to the identification of genes responsible for these diseases. This is the first step towards the
development of treatments for affected individuals.
Research achievements (from final report):
This program was based around the use of genetics and genomics techniques to find disease genes and to
describe disease processes. We have described the genetic basis of many new diseases. These include
epilepsies, mitochondrial disease and rare mendelian diseases. We have also worked with cancer biologists and
have determined breakpoints in myeloid leukaemias, analysed transcriptional differences in tumours. We have
also worked in malaria and have performed an ENU mutagenesis screen that has identified 80 malaria survival
mutants. We have implicated platelets in survival to malarial infection and delineated the functional molecular
basis., We also work on the development of statistical and genomic technologies. This has led to improvements
in the way metabolomics data is analysed. We improved the determination the ploidy of tissue and cell lines
using sequence data. We have also been involved in the statistical analysis of biological imaging, especially in
the field of malaria. Many studies on the construction and analysis of biological networks has been carried out
in cancer cells and micro-organisms., There has also been fundamental technology development that has
resulted in the production of statistical packages to further analyse microarray data. We have contributed to the
analysis of genomic sequence data and were involved in the wallaby sequencing project where the genomic
sequence of the wallaby was first produced. We have produced packages to analyse RNAseq data.
Expected future outcomes:
We will continue to contribute to the development of statistical analysis in biology, particularly genetics and
genomics, , continue working to identify genes and therapies for rare mendelian diseases. Our knowledge of
protective genes against malaria will be used to develop new antimalarial drugs that target the host, not the
parasite.
Name of contact:
Simon Foote
Email/Phone no. of contact:
simon.foote@mq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1007706
Start Year: 2011
CIA Name: Prof Helen Rizos
End Year: 2014
Admin Inst: Macquarie University
Grant Type: NHMRC Project Grants
Main RFCD: Cell Development, Proliferation and Death
Total funding: $302,981
Title of research award:
Dissecting PTEN-regulated pathways in the genesis of melanomaDissecting PTEN-regulated pathways in the
genesis of melanoma
Lay Description (from application):
Melanoma is a major Australian health problem. It is the third most common cancer in men and women and
has a disproportionately heavy impact on productive years of life. The PTEN phosphatase is one of the most
common targets for inactivation in melanoma. The precise role of PTEN and its contribution to melanoma
development have not been thoroughly explored. This work will highlight potentially novel pathways and
molecules that are likely to be critical in the genesis of melanoma and to the rational approach to targeted
therapy.
Research achievements (from final report):
Despite significant improvements in the response and survival of metastatic melanoma patients treated with
selective BRAF or c-Kit inhibitors the majority of patients will progress within twelve months and resistance
remains a barrier to better patient outcomes. Activation of the PI3K-PTEN-AKT survival pathway contributes
to melanoma resistance to BRAF and c-Kit inhibitors and we have confirmed that this pathway is frequently
activated in melanomas via activating mutations in upstream regulators and loss of function mutations in the
PTEN tumour suppressor. We and others have shown that although pre-existing inactivating mutations in
PTEN do not preclude clinical responses to BRAF inhibitors the loss of this tumour suppressor and activation
of the PI3K-PTEN-AKT cascade diminishes melanoma cell sensitivity to BRAF and c-Kit inhibitors. We also
examined treatment strategies that may prove effective in melanoma patients that had progressed on BRAFinhibitor and c-Kit inhibitor therapy. We confirmed that the concurrent inhibition of the BRAF and PI3KPTEN-AKT pathways was effective at promoting melanoma cell death and circumvented resistance in
melanoma cell models with acquired resistance to BRAF or c-Kit inhibitors. These data indicate that durable
response in melanoma patients requires combination first-line therapy that selectively inhibits multiple
proliferative and survival pathways.
Expected future outcomes:
We are continuing to explore the nuclear and cytoplasmic functions of PTEN in melanoma. We are also
investigating the role of PTEN in regulating pathway activity and melanoma cell survival in response to
clinically-active inhibitors.
Name of contact:
Helen Rizos Helen Rizos
Email/Phone no. of contact:
helen.rizos@mq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 235606
Start Year: 2003
CIA Name: A/Pr Georgina Clark
End Year: 2005
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: NHMRC Project Grants
Main RFCD: Cellular Immunology
Total funding: $489,750
Title of research award:
Members of the CMRF-35 Leukocyte Receptor Complex on Human Chromosome 17q22-24 Modulate
Immune FunctionMembers of the CMRF-35 Leukocyte Receptor Complex on Human Chromosome 17q22-24
Modulate Immune Function
Lay Description (from application):
We have identified and characterized a group of proteins on the surface of different white blood cells called the
CMRF-35 molecules. We hypothesize that these molecules play a role in regulating an immune response by
acting as thermostat molecules i.e. molecules able to trigger or inhibit the immune response. This project aims
to define the role of two of these molecules in regulating white blood cells in their response to foreign
molecules or antigens. This project will have significant impact on understanding whether these triggering and
inhibitory signals initiated from the CMRF-35 molecules effects i) how the cells divide, ii) what molecules are
secreted by the cells, iii) whether the cells can mature or iv) whether a cell survives or dies. Some of the
molecules involved in sending these signals will be identified. The ability to trigger or inhibit cellular effects
through these molecules may be important in some forms of myeloid leukemia and in the ability to help
manipulate the immune response to fight tumors.
Research achievements (from final report):
The research focused on a family of leucocyte surface molecules, previously called the CMRF-35 family. Our
work during this grant period resulted in it being renamed the CD300 family by the Human Leucocyte
Differentiation Antigen Workshop. The function of these molecules is to balance the immune response by
delivering triggering or inhibitory signals. Two CD300 members are expressed on multiple leucocyte
populations, whilst other CD300 family members are expressed predominantly on cells of the myeloid and
dendritic cell lineages. We have shown that antibodies that bind CD300a and CD300c are able to identify the T
effector memory subpopulation from peripheral blood, whilst another monoclonal antibody that binds the
CD300e molecule that is expressed only by monocytes is able to purify cells that are capable of differentiating
into monocyte derived dendritic cells. Thus members of this family have applications for regulating immune
responses and as reagents, the ability to improve therapeutic products.
Expected future outcomes:
The altered T effector memory population documented in psoriasis has major implications for understanding
this chronic skin disease. Our monocyte derived dendritic cell populations may be tested in immunotherapeutic
trials. Other CD300 molecule functions are being defined.
Name of contact:
Georgina Clark
Email/Phone no. of contact:
gclark@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 281803
Start Year: 2004
CIA Name: Prof Derek Hart
End Year: 2006
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: NHMRC Project Grants
Main RFCD: Oncology and Carcinogenesis
Total funding: $432,750
Title of research award:
Activated Dendritic Cell Monoclonal Antibodies as Therapeutics to Prevent Graft Versus Host
DiseaseActivated Dendritic Cell Monoclonal Antibodies as Therapeutics to Prevent Graft Versus Host Disease
Lay Description (from application):
A New Therapy to Prevent Graft versus Host Disease in Bone Marrow Transplantation Bone marrow
transplants often fail due to the immune reaction of the grafted donor cells against the patient (graft versus host
disease). Current treatments to prevent this do not always work and have serious side-effects or other
disadvantages.The immune reaction is induced by activated dendritic cells which are the primary stimulators of
the body's defences against foreign invaders. We have developed antibodies in mice that react with human
activated dendritic cells and prevent them from inducing immune responses in the test-tube. These antibodies
are also likely to be effective in patients, but cannot be used in their present form because mouse antibodies
induce an undesirable immune response in humans. We therefore plan to convert them to resemble human
antibodies ("antibody engineering").Antibodies that react with other types of cell in the body are already used
to treat or prevent a variety of conditions, including graft versus host disease, but no one has developed a
therapeutic antibody against activated dendritic cells. We are applying to the NHMRC for funding to
"engineer" our antibodies and to test them in test tube experiments and also in mouse models of graft versus
host disease. We also plan to study the changes in blood levels of activated dendritic cells in bone marrow
transplnt patients. This will provide information on the best time to use our new therapeutic antibodies to
prevent graft versus host disease. The aim of this grant application will have been achieved if, after three
years, we have a new antibody ready for testing in bone marrow transplant patients.
Research achievements (from final report):
We have made significant progress towards a novel therapy that targets activated dendritic cells (DC) for the
prevention of graft versus host disease (GVHD) in allogeneic bone marrow transplantation. Our main outcomes
are: , (a) Finding that detection of circulating activated DC predicts which transplant patients are likely to
develop acute GVHD. This exciting data provides the basis for the first predictive test for acute GVHD and the
first clinical evidence to justify early intervention to prevent GVHD. , (b) Our human-SCID mouse model of
GVHD has been validated and used to show that targeting human DC in vivo with antibodies prevents GVHD.,
(c) We have successfully completed the first step in generating therapeutic antibodies that target activated DC.
We have generated stable CHO cell transfectants expressing chimeric human IgG1 and IgG4 forms of the
CMRF-44 and CMRF-56 monoclonal antibodies (mAbs). The chimeric mAbs have retained specificity for the
respective DC activation antigens but, as expected, they have low avidity and functional activity. We are
therefore affinity maturing the CMRF-44 mAb to increase its avidity and functional activity., (d) The MMRI
has developed clinical trial infrastructure, including a new biotherapeutics facility, manufacturing and quality
staff. A DC immunotherapy phase 1 clinical trial in prostate cancer is underway. Commercial manufacture of
the chimeric human IgG4 CMRF-56 antibody for clinical trial is near completion. Specific planning for a trial
of anti-activated DC antibody therapy for GVHD is underway. Essential preclinical experiments and toxicity
studies have been clarified.
Expected future outcomes:
We anticipate testing one of our candidate therapeutic antibodies that target activated DC in clinical trials for
safety and efficacy. Given a successful outcome in trials and adequate financial backing from industry we
expect that anti-activated DC therapy will improve outcomes for patients with leukaemia and other conditions.
Name of contact:
Professor Derek Hart
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
dhart@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 288701
Start Year: 2004
CIA Name: A/Pr Jean-Pierre Levesque
End Year: 2006
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: NHMRC Project Grants
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $472,750
Title of research award:
Role of neutrophil proteases and their inhibitors in haematopoietic stem cell mobilisationRole of neutrophil
proteases and their inhibitors in haematopoietic stem cell mobilisation
Lay Description (from application):
Mobilisation is the enforced migration of blood forming cells (haemopoietic stem cells) from the bone marrow,
where they normally reside, into the blood. The most common agent used to induce mobilisation of
haemopoietic stem cells is a cytokine called G-CSF. In recent years, the number of transplantations performed
with mobilised blood stem cells has exceeded those performed with bone marrow aspirates. The simplicity of
the procedure (daily injections of G-CSF, absence of bone marrow aspiration), better patient recovery and
survival, lower costs have all contributed to the success of this procedure. Despite its common use in clinics to
rescue cancer patients undergoing high-dose chemotherapy, the reasons why haemopoietic stem cells mobilise
are still not fully understood. It is known that haemopoietic stem cells stay in the bone marrow because they
express 'adhesive' molecules on their surface. In pioneering work, this laboratory has shown that cytokines such
as G-CSF increases the number of neutrophils (a type of white blood cell) in the bone marrow. These
neutrophils release enzymes (known as proteases) which cut into pieces the 'adhesive' molecules and other
proteins responsible for the retention of blood forming cells within the bone marrow. This project aims to
further these investigations to include both the role of proteases and their naturally-occurring inhibitors in the
mobilisation of blood forming cells. Particularly, we will investigate how the expression of serpins and TIMPs,
two families of protease inhibitors, is regulated in the bone marrow during mobilisation and how these
inhibitors control the activity of proteases responsible for the mobilisation of blood forming cells. This
knowledge may lead to the design of new treatments that induce more efficient mobilisation and ultimately
improve the success of haemopoietic stem cell transplantation.
Research achievements (from final report):
Mobilisation is the enforced migration of blood forming cells (haematopoietic stem cells) from the bone
marrow, where they normally reside, into the blood. Mobilisation is such a powerful technique to obtain large
numbers of stem cells that the number of transplantations performed with mobilised blood stem cells now
largely exceeds the number of transplantations made with traditional bone marrow aspirates. The most
common agent used to induce mobilisation of haematopoietic stem cells is a human growth factor called GCSF (granulocyte colony-stimulating factor). The simplicity and safety of the procedure (daily injections of GCSF, absence of bone marrow aspiration), better patient recovery and survival, and lower costs have all
contributed to its success. Despite its common use in clinics to rescue cancer patients undergoing high-dose
chemotherapy, the reasons why haematopoietic stem cells mobilise into the blood are still not fully understood.
In pioneering work, we have found that G-CSF causes stem cell mobilisation through the release of a class of
enzymes (known as proteases) which cut into pieces the 'adhesive' molecules and other proteins responsible for
the retention of stem cells within the bone marrow. In this project we have also discovered that this is possible
because naturally-occurring inhibitors of proteases stopped being produced in the bone marrow during
mobilisation. This knowledge may lead to the design of new treatments that induce more efficient mobilisation
of stem cells and ultimately improve the success of bone marrow reconstitution in cancer patients by
transplantation.
Expected future outcomes:
Our research has contributed to the discovery that a new class of drugs (called chemokine antagonists) mobilise
haematopoietic stem cells very efficiently, particularly when combined with G-CSF. One of these new drugs,
called AMD3100 has been successfullty evaluated for its mobilising potential.
Name of contact:
NHMRC Research Achievements - SUMMARY
Jean-Pierre Levesque
Email/Phone no. of contact:
jplevesque@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 331966
Start Year: 2006
CIA Name: Dr Penelope Jeffery
End Year: 2009
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Oncology and Carcinogenesis
Total funding: $276,750
Title of research award:
Cell surface mucins modulate epithelial cell growth and apoptosis of normal mucosal wound repair and
epithelial cancersCell surface mucins modulate epithelial cell growth and apoptosis of normal mucosal wound
repair and epithelial cancers
Lay Description (from application):
Not Available
Research achievements (from final report):
This fellowship has enabled the recipient to undertake an intensive full-time training program in biomedical
research. The trainee has acquired skills in the manipulation and study of animal models of disease and
advanced techniques in immunology and molecular biology. The fellow has also developed skills in scientific
writing and the success of this is evident by the fact that the fellow received an NHMRC project grant (as the
chief investigator A) and several smaller grants during the course of her training fellowship. The fellow helped
to phenotype a unique mouse model that was created in her laboratory and that has shown to have an increased
susceptibility to inflammatory bowel disease (IBD). The fellow has also used other models of this disease to
test potential new agents for the treatment of IBD and has translated these findings by using immune cells
taken from IBD patients and examining the mechanisms underpinning the anti-inflammatory effects of novel
agents. These impacts are significant as novel treatments for IBD are urgently required and the work arising
from this fellowship has garnered interest from the pharmaceutical industry.
Expected future outcomes:
This work will continue as the fellow has secured future funding. The novel agents identified during the
fellowship as being anti-inflammatory in mouse models of IBD will be further studied with the goal of
employing them in clinical trials with IBD patients.
Name of contact:
Penny Jeffery
Email/Phone no. of contact:
pjeffery@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350406
Start Year: 2005
CIA Name: Dr Ingrid Winkler
End Year: 2007
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: NHMRC Project Grants
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $472,500
Title of research award:
Role of selectins and their receptors in the regulation of the haemopoietic systemRole of selectins and their
receptors in the regulation of the haemopoietic system
Lay Description (from application):
The production of blood cells occurs in the bone marrow. This process depends on the controlled proliferation
and development of rare and multipotent precursors called haemopoietic stem cells, and involves a subtle
balance between the positive regulation of proliferation and growth inhibition necessary to prevent blood cell
overproduction and leukaemia. We have recently shown that two related proteins expressed at the surface of
cells of the bone marrow vasculature negatively regulate blood cell formation. These proteins, called P-selectin
and E-selectin, are essential to regulate the migration of immune cells into lymphoid organs and inflamed
tissues. We have found that these selectins also mediate the adhesion of haemopoietic stem cells in the bone
marrow vasculature, inhibit their proliferation and kill some of their progeny. This project includes three
specific aims to: 1) characterise the role of P-selectin and E-selectin in vivo in the regulation of blood cell
formation, 2) understand the molecular mechanisms inside haemopoietic stem cells which are responsible for
the growth inhibition and cell death in response to selectins, and 3) identify the receptors which are responsible
for these effects of selectins on haematopoietic stem cells. These findings will give us a better understanding of
how blood formation is regulated in vivo and how these interactions are perturbed during the emergence of
leukaemia.
Research achievements (from final report):
The production of all blood and immune cells occurs in the bone marrow. This process depends on the
controlled proliferation and development of a rare and multipotent precursor cell called haemopoietic stem cell,
and involves a subtle balance between the positive regulation of proliferation and growth inhibition necessary
to prevent blood cell overproduction and leukaemia. During the course of this project, we have identified a
protein expressed at the surface of bone marrow blood vessels which regulates the speed at which
haematopoietic stem cells divide in the bone marrow. This protein, a member of the selectin family, is well
known to regulate the migration of immune cells into lymphoid organs and inflamed tissues. We have
discovered that removal of this protein in mice, delays the speed at which haematopoietic stem cell divide in
the bone marrow. As a result, haematopoietic stem cells are more resistant to irradiation and chemotherapy
treatments used in cancer patients. Since haematopoietic stem cells can be severely damaged by chemotherapy
and radiotherapy, leading to life threatening to blood and bone marrow failure, our discovery opens the
possibility of using selectin blockers to decrease chemotherapy and radiotherapy toxicity on normal
haematopoietic stem cells and accelarate recovery from these treatments.
Expected future outcomes:
The great clinical potential of discovery as been recognised with the award of a new NHMRC Project Grant to
investigate the protective effect of E-selectin inhibitors on haematopoietic stem cells in vivo. If conclusive, the
E-selectin antagonists could be use to decrease the morbidity associated associated with high doses of
chemotherapy and radiotherapy in patients.
Name of contact:
Ingrid G Winkler
Email/Phone no. of contact:
iwinkler@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 382308
Start Year: 2006
CIA Name: Prof Derek Hart
End Year: 2008
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: NHMRC Project Grants
Main RFCD: Cellular Immunology
Total funding: $378,108
Title of research award:
Cytokine production by human dendritic cells - Is less more?Cytokine production by human dendritic cells - Is
less more?
Lay Description (from application):
Dendritic cells (DC) are specialist white blood cells responsible for initiating and coordinating immune
responses against pathogens and cancer. DC act as sentinels of the immune system and are found throughout
the body where they are in constant surveillance for infections or "danger signals". Once armed they traffic to
the lymph nodes, where they activate T lymphocytes and NK cells, which are then responsible for mounting an
attack against the infection or tumour. The complex mechanisms of how dendritic cells respond to "danger",
and how they direct T and NK cells to induce specific immune responses appropriate for a particular infection
are poorly understood. Most of our current knowledge of DC has been obtained from mouse studies, and it is
believed that secretion of cytokines by dendritic cells play an important role. Human dendritic cells have been
difficult to identify, however we have pioneered methods to isolate and characterise them from human tissue.
We will therefore investigate the production of cytokines from human DC subsets and the role they play in the
induction of immune responses. DC can be instructed in the test tube to recognise a cancer and mount an
immune response, and this is a promising new therapy for cancer. Our work will uncover fundamental
information about the most potent danger signal, the type of DC and the most important cytokines for inducing
immune responses against cancers, and will therefore assist in the development of cancer vaccines.
Research achievements (from final report):
Dendritic cells (DC) are white blood cells that initiate and direct immune responses, including responses
against viruses and cancers. In mice, DC are emerging as complex populations with several individual subsets
identified as having specialised functions. Unfortunately, human DC have been poorly studied due to their low
frequency, a lack of distinguishing markers, and limited access to human tissues. We had previously identified
several phenotypically distinct human blood DC subsets, including the rare CD141+ subset. After considerable
effort, we developed procedures to isolate sufficient highly pure human blood DC to study their function for
the first time. We demonstrated that the phenotypically distinct human DC subsets were also functionally
distinct, highlighting the complexity and specialised roles of human DC subtypes. Our data provide
fundamental new information establishing the CD141+ DC subset, in particular, as a novel but highly relevant
functional human DC subset found in bone marrow, blood, tonsil,lymph node and skin. We discovered that
CD141+ DC have functional features that suggest they have a special capacity to process targets and induce T
cell immune responses against cancer and viruses. Importantly, our data resolves an elusive aspect of concern
to all immunologists - the identification of human CD141+ DC as the mouse CD8+ DC equivalent. The latter
play a crucial role in the induction of protective immune responses against tumors and viruses and have been
the subject of considerable investigation. This wealth of mouse DC knowledge can now be translated into
human practice. We predict that the CD141+ DC subset is likely to play the major role in the induction of
human anti-tumor and anti-viral immune responses. As such, they may be the most appropriate human DC
subset to target for in vivo vaccination. This has far reaching implications for the design of therapeutic cancer,
viral (eg. HIV) and other pathogen (e.g. malaria) vaccines.
Expected future outcomes:
These findings will be used to develop new vaccine strategies that target the CD141+ DC subset directly in
vivo for the treatment of cancer and pathogens.
Name of contact:
Derek Hart
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
dhart@uq.edu.au
dhart@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 434507
Start Year: 2007
CIA Name: A/Pr Alison Rice
End Year: 2009
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: NHMRC Project Grants
Main RFCD: Haematology
Total funding: $434,510
Title of research award:
Antibody-mediated Dendritic Cell Depletion to Attenuate GVHDAntibody-mediated Dendritic Cell Depletion
to Attenuate GVHD
Lay Description (from application):
Not all patients with leukemia will be cured by chemotherapy. Stem cell transplantation improves their chances
of survival. Stem cell transplantation requires intensive chemotherapy and radiotherapy to eradicate the
underlying disease and infusion of healthy stem cells to provide an anti-leukemic effect and normal blood cells.
Recovery from transplantation is not straightforward. Recovery can be hampered by the immunological
reaction of the donor cells against the patient (Graft versus Host Disease [GVHD]), despite
immunosuppression. GVHD produces serious damage to the internal organs and lining of the mouth and gut.
Recovery can also be circumvented by leukemic relapse. GVHD is associated with an increased risk of death
and dying after transplantation. To date therapy for GVHD has relied on eliminating the T cells that cause the
disease. However for T cells to cause damage they must first be primed with antigen presented on activated
dendritic cells. The intensive conditioning therapy required to eradicate the underlying disease before
transplantation also activates dendritic cells. Our project seeks to investigate the effects of lethal and non-lethal
conditioning on dendritic cells with the aim of validating the use of antibodies designed to deplete activated
dendritic cells as therapy for graft versus host disease.
Research achievements (from final report):
We found that a single dose of the new drug can delay death from graft versus host disease in a mouse model
of bone marrow transplantation. The new drug does not prevent the new donor immune and blood system
developing and functioning normally in the transplant recipient. We are now conducting experiments to
determine if drug alters the function of B cells. We also conducted experiments in the laboratory to determine
exactly how the new drug works. We found that the drug alters the growth pattern of the immune cell that is
involved in the development of graft versus host disease but it does not alter the growth of the immune cells
that are needed to fight infection or kill leukaemic cells. We are encouraged that this new drug will protect
against graft versus host disease without compromising immune defence.
Expected future outcomes:
We hope that this new drug will soon enter clinical trial and be selected as the treatment of choice to prevent
graft vesrus host disease whist retaining the beneficial anti-leukaemia effect.
Name of contact:
Associate Professor Alison Rice
Email/Phone no. of contact:
arice@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 434510
Start Year: 2007
CIA Name: Dr Slavica Vuckovic
End Year: 2009
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: NHMRC Project Grants
Main RFCD: Tumour Immunology
Total funding: $425,697
Title of research award:
Targeting Human Dendritic Cells in a Multiple Myeloma Humanized NOD/SCID ModelTargeting Human
Dendritic Cells in a Multiple Myeloma Humanized NOD/SCID Model
Lay Description (from application):
Adoptively transferred dendritic cells (DC) loaded with tumor associated antigen (TAA) have been shown to
induce anti-tumor immunity in animal models; however, their therapeutic efficacy in cancer patients has not
been established. Protective immunity has failed in the tumor-bearing host and the ability of human DC to
induce anti-tumor responses in the abnormal environment of the cancer patient requires further investigation.
Due to the limited capacity to investigate the DC-tumor interaction in patients, humanized animal models
containing human DC and tumor provide an opportunity to obtain important new information. We propose to
develop multiple myeloma (MM) as a human tumor in our humanized (hu)NOD/SCID model containing
human DC, and to use this in vivo MM-huNOD/SCID model to restore immunity by correcting the human DCtumor interaction.This knowledge will act as a fast track to select and design a new (simplified) DC-based
immunotherapy to treat cancer patients and will be translated directly into our MM clinical trials program,
potentially by targeting human DC based on CD205 recognition.
Research achievements (from final report):
Allo-transplantation of haematopoietic cells, a front-line therapy for cancer patients, is associated with the high
incidence of mortality caused by graft-versus-host disease (GVHD). Studies using a "classical mouse model",
suggested that host antigen presenting cells, such as dendritic cells (DC) and prime allo-T cell responses,
induce GVHD. Although manipulation of DC is an attractive strategy to reduce severity of GVHD, such
manipulations are impossible in humans and mouse studies cannot be readily translated to humans. To
overcome this limitation, we developed humanized (hu)NOD/SCID mice repopulated with human DC derived
from transplanted hematopoietic CD34+ stem cells (Vuckovic et al. Exp Hematol.1502-12;36;2008). Using our
humanised NOD/SCID mouse model, we reported unexpected findings that found activated DC within bone
marrow (primary lymphoid organs) are more effective than DC within the spleen (secondary lymphoid organ)
in inducing effector allo-T cell responses. This opens a new avenue to define the type of DC that orchestrate
allo-T cell responses and explore strategies to modulate their number and/or activity, as a means of suppressing
allo-T cell responses and associated GVHD., We also developed a new model of human MM based on
transplantation of MM cells into preconditioned NOD/SCID mice. This model provides a practical system to
dissect MM pathology and validate anti-MM therapy (manuscript in preparation).
Expected future outcomes:
This research will provide new knowledge for cellular and pharmacological manipulations to suppress lifethreatening graft-versus-host disease (GVHD) in transplanted cancer patients and improve diagnosis and
management of MM, the most common bone cancer in those older than 50 years of age.
Name of contact:
Slavica Vuckovic
Email/Phone no. of contact:
slavica.vuckovic@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 434513
Start Year: 2007
CIA Name: Prof Derek Hart
End Year: 2009
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: NHMRC Project Grants
Main RFCD: Haematology
Total funding: $609,760
Title of research award:
A Phase 1 Clinical Trial of a Human Chimeric Anti-Activated DC Antibody to Prevent AGVHD in high risk
allo HSCT.A Phase 1 Clinical Trial of a Human Chimeric Anti-Activated DC Antibody to Prevent AGVHD in
high risk allo HSCT.
Lay Description (from application):
Bone Marrow transplants provide life saving therapy for leukaemias, lymphomas and other life threatening
blood disorders. One of the major life threatening complications is acute graft versus host disease (AGVHD) in
which the doner immune system damages the patient's skin, liver and gut, amongst other tissues. Dendritic cells
initiate and direct immune responses. We have shown that dendritic cells are central to the initiation of
AGVHD and have shown that a marker called CMRF-44 is expressed on activated dendritic cells before
AGVHD emerges. We have developed potential new therapeutic antibodies that target activated dendritic cells
and shown that they are effective in preclinical studies. This project will further validate these antibodies, then
test their safety and their ability to prevent AGVHD in patients. The trial will also test whether they have the
expected additional beneficial effect of preserving protective anti-viral and anti leukaemic immune responses.
Research achievements (from final report):
In this project we developed a new type of antibody drug to prevent graft versus host disease (GVHD). GVHD
is a serious, therapy limiting complication of allogeneic haematopoietic stem cell transplantation (alloHSCT,
previously known as "bone marrow transplantation") which is used as a last-chance therapy for some
leukaemias and other blood disorders. Existing drugs for GVHD are highly immunosuppressive which places
alloHSCT patients at risk of sometimes fatal infections. Immunosuppressive drugs also impair the desired
"graft versus leukaemia" effect of alloHSCT, without which there is no point in risking alloHSCT therapy. ,
Our new antibody drug has a significant advantage over current non-specific immunosuppressive treatments
for preventing GVHD because it does not impair T lymphocytes, which are the key components of the immune
system that protect the patient from infection and also carry out the desired graft versus leukaemia effect. We
have developed the drug to the point that it is effective in laboratory experiments and mouse experiments.
However, it is clear that improvements can be made and work towards this end is currently underway,
supported by an Australian commercial partner, with the overall aim of making the drug available to patients
world-wide.
Expected future outcomes:
The anticipated future outcomes are: (1) Antibody engineering to further improve efficacy of our lead antibody
drug; (2) Completion of preclinical testing (in vitro and in vivo in mice); (3) Filing of relevant patent claims;
(4) Testing in first-in-human phase 1/2 clinical trial; (5) Further clinical trials and commercialization.
Name of contact:
David Munster
Email/Phone no. of contact:
dmunster@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 454506
Start Year: 2007
CIA Name: Dr Nigel Waterhouse
End Year: 2009
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: NHMRC Project Grants
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $335,065
Title of research award:
Molecular mechanisms of death in cells with defective apoptotic pathwaysMolecular mechanisms of death in
cells with defective apoptotic pathways
Lay Description (from application):
The body protects itself from cancer by killing any cell that poses a risk of becoming a tumour. The body kills
these cells via a carefully orchestrated sequence (or pathway) of events, however many cancer cells have
defects in cell death pathways that has permitted them to survive even though they have been told to die. In this
proposal we set out a research program to investigate how to kill cancer cells that don't want to die. Various
tumour cells have been shown to have increased levels of Bcl-2, a proto-oncogene that blocks cell death
induced by diverse stimuli. Cells that over-express Bcl-2 are also resistant to cytotoxic drugs. Understanding
how to bypass Bcl-2 (or proteins that block cell death in tumours) will lead to a better understanding of cell
death/cell survival and allow us to explore the possibility of tailoring treatment for patients in which specific
defects in death pathways have been identified in their cancer cells.Cytotoxic lymphocytes (CL) are cells of the
immune system that defend the body from cancer by specifically attacking and killing tumor cells. We have
been pioneering studies of CL:tumour interactions in which we can define the morphology and kinetics of
critical events in cell death and have shown that CL have the ability to kill target cells that over-express Bcl-2.
Following the aims in this proposal, we will understand the mechanisms by which cytotoxic lymphocytes kill
target cells that have defects in classical cell death pathways. These studies will therefore define alternative
pathways to cell death in the event that a key component of the preferential pathway to cell death is
inoperative. Since cytotoxic lymphocytes use a variety of ways to kill their targets and tumors may contain
multiple defects in cell death pathways, we will explore which are the key defects, or the combination of
multiple defects, in cell death pathways that prevent cytotoxic lymphocyte mediated cell death and permit
tumour survival in vivo.
Research achievements (from final report):
Bcl-2 is a proto-oncogene that is a significant clinical problem for cancer therapy because it promotes cell
survival and renders cells resistant to current chemotherapy. Consequently there is significant interest in
understanding how to kill cancer cells that over-express Bcl-2. Bcl-2 blocks the mitochondrial pathway to
apoptosis, but does not block apoptosis by cytotoxic lymphocytes, cells of the immune system which currently
offer the best clinical outcome for chemoresistant cancers. This grant set out to understand how cytotoxic
lymphocytes kill Bcl-2 overexpressing cells by apoptosis. We showed that cytotoxic lymphocytes use
granzyme B to cleave Bid which is blocked by Bcl-2, and caspase-3 which is blocked by XIAP. Consequently
neither Bcl-2 nor XIAP (another anti-apoptotic protein over-expressed in cancer) alone can block cytotoxic
lymphocyte- induced apoptosis. However we found that overexpression of both proteins together can block
cytotoxic lymphocyte induced death in humans. This may be one way that cancer cells resist clearance by the
body's own immune system.
Expected future outcomes:
These studies suggested that Bcl-2 will only contribute to cancer progression if XIAP is also over-expressed.
We have now embarked on studies to understand how these two proteins synergise to contribute to cancer
progression, and how neutralising Bcl-2 to resensitise cancer cells to immune mediated killing.
Name of contact:
Nigel Waterhouse
Email/Phone no. of contact:
nwaterhouse@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 488811
Start Year: 2008
CIA Name: Dr Penelope Jeffery
End Year: 2010
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: NHMRC Project Grants
Main RFCD: Gastroenterology
Total funding: $243,117
Title of research award:
Novel applications of ghrelin peptides in mouse models of inflammatory bowel diseaseNovel applications of
ghrelin peptides in mouse models of inflammatory bowel disease
Lay Description (from application):
Inflammatory bowel disease (IBD) is a debilitating, chronic condition that often affects patients in the primes
of their lives. A limited number of treatments are currently available for these patients and those that are
available often have serious side effects, including growth restriction in children. Ghrelin is a natural hormone
that has been shown to suppress many features of IBD. This project will investigate the potential of ghrelin as a
new treatment for inflammatory bowel disease.
Research achievements (from final report):
Ghrelin is a naturally occurring hormone that is produced predominantly in the stomach. Ghrelin stimulates
appetite and growth hormone release and has recently been described as an anti-inflammatory hormone. In this
project we have determined that ghrelin peptides have mild to moderate anti-inflammatory properties in mouse
models of inflammatory bowel disease. Ghrelin treatment reduced histopathology and improved clinical colitis
scores in a mouse colitis model which is induced using a luminal toxin. We have determined that in this type of
colitis, ghrelin is able to suppress activation of macrophages and suppress the secretion of the proinflammatory cytokines including IL-17 from immune cell cultures. In addition to this, ghrelin increases
proliferation and decreases apoptosis of intestinal epithelial cells. Ghrelin treatment also reduces pathology and
improves disease activity index in a different model of colitis which is driven by intestinal endoplasmic
reticulum (ER) stress. Using human cell lines, we performed studies to determine mechanisms underlying
ghrelin's effects and have determined that ghrelin activates classical growth factor pathways in epithelial cells.
For the first time, we have also shown that ghrelin inhibits ER stress in human colon cells. New treatments for
IBD are urgently required as current therapies often have severe side effects. Ghrelin and ghrelin modulating
agents deserve further evaluation as anti-inflammatory agents in IBD.
Expected future outcomes:
It is anticipated that development of stable ghrelin modulators will be developed and these will have a stronger
anti-inflammatory effect than natural ghrelin.
Name of contact:
Dr Penny Jeffery
Email/Phone no. of contact:
pjeffery@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 488817
Start Year: 2008
CIA Name: Dr Ingrid Winkler
End Year: 2011
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: Career Development
Fellowships
Main RFCD: Haematology
Total funding: $380,559
Title of research award:
Interactions between haematopoietic, bone, vascular and endocrine systems control stem cell fate and
mobilizationInteractions between haematopoietic, bone, vascular and endocrine systems control stem cell fate
and mobilization
Lay Description (from application):
Haemopoietic stem cells (HSC) normally reside in the bone marrow (BM) where they make blood and immune
cells. We can force HSC to move from the BM into the blood, a process called mobilisation, used to collect
large numbers of HSC for transplantation into cancer patients. My research involves identifying factors that
control HSC fate within the BM (that is survival, growth, differentiation) and what happens during
mobilisation to force them to leave with the aim of improving transplant success.
Research achievements (from final report):
About 1/3 of cancer patients will suffer from an infection during or soon after their chemotherapy. This
happens because chemotherapy is made to kill rapidly growing cells, like cancer cells (which are the target) but
chemotherapy also kills the normal cells in the bone marrow whose job it is to replenish your blood and
immune system. The damage to these normal cells leaves a patient very vulnerable to infection. , In Australia
alone, over 5000 cancer patients will be hospitalised each year solely due to the side effects of their
chemotherapy treatment, not their underlying disease. , To help these patients, my research has focused on
ways to protect the healthy cells in the BM from the chemotherapy drugs. In this project I discovered the
molecular switch the body uses to make these bone marrow cells either go to sleep (which means they are
resistant to chemotherapy), or wake up and regenerate the blood and immune system now. Even better I can
now achieve this with a small antagonist. When I give this antagonist, normal BM cells go to sleep and are
protected from chemotherapy, when I remove the antagonist they wake up., Thanks to my NHMRC funding,
under which I made these (now patented) discoveries, I am now in a position to attract commercial funding
from overseas to continue this work in Australia. For patients these discoveries may make the chemotherapytreatment itself far less dangerous, enabling more rapid return to work and family, while at the same time
decreasing overall healthcare costs.
Expected future outcomes:
My research has discovered a way to limit some of the severe side-effects of chemotherapy. For patients this
research may make their chemotherapy-treatment far less dangerous, so they can more rapidly return to work,
re-engage with their community, with overall lower hositalisaton and healtcare costs.
Name of contact:
Ingrid Winkler
Email/Phone no. of contact:
iwinkler@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 488818
Start Year: 2008
CIA Name: Prof Janet Hardy
End Year: 2009
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: SRDC - Research
Main RFCD: Pharmaceutical Sciences and Pharmacy
Total funding: $49,135
Title of research award:
An evaluation of the validity of measureing salivary oxycodone concentrations for pharmacokinetic studies in
patientsAn evaluation of the validity of measureing salivary oxycodone concentrations for pharmacokinetic
studies in patients
Lay Description (from application):
In many countries, oxycodone is replacing morphine as the opioid of first choice for the treatment of moderate
to severe pain. Despite this, very little is known about how the drug is processed in the body or how its ability
to control pain is affected by such factors as other drugs, age or organ function. Studies to determine this
usually require multiple blood tests from individual patients over set time periods. Our team is able to measure
drug levels in saliva and has shown this to be a valid substitute for the measurement of drug levels in blood.
Furthermore, one of us has developed a computer modelling system that shows how drugs are handled in the
body using only a few samples from each patient. Palliative care patients are generally frail and unwell. We are
reluctant to expose them to invasive tests such as repeated blood sampling. If we can prove that saliva sampling
is as good as blood sampling, we will have identified a simple non-invasive means of greatly increasing our
knowledge of oxycodone and how it behaves in individual patients. This in turn may allow us to tailor drug
doses according to the unique characteristics of each patient and to optimise their pain control.
Research achievements (from final report):
In attempting to validate saliva as an alternate matrix to plasma when undertaking pharmacokinetic studies in
cancer patients taking delayed release oxycodone tablets, we have shown very high concentrations of
oxycodone and its primary metabolite in saliva, but no correlation between drug concentrations saliva and
plasma. Similarly, there was no correlation between salivary pH and distribution between plasma and saliva for
either oxycodone or the metabolite. This raises the possibility of the presence of an active transporter, acting
independently of salivary pH, being responsible for the appearance of higher concentrations of oxycodone in
saliva than blood. We also showed that patients prefer to provide saliva rather than plasma samples unless they
have in-dwelling central lines from which blood can be drawn and that it is possible to collect a large number
of samples from patients attending an oncology out-patient department that can be used subsequently for
pharmacokinetic studies.
Expected future outcomes:
During the course of this study we collected a large number of plasma samples from patients on oxycontin
across a range of doses and dosing intervals. Oxycodone concentrations determined from these samples will be
used to evaluate population pharmacokinetics (PKs) of the parent drug and metabolite using NONMEM
software.
Name of contact:
Professor Janet Hardy
Email/Phone no. of contact:
janet.hardy@mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 488821
Start Year: 2008
CIA Name: Dr Falak Helwani
End Year: 2011
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: Early Career Fellowships
(Australia)
Main RFCD: Haematology
Total funding: $178,524
Title of research award:
Cellular and molecular determinants that regulate osteoblasts at the endosteal niche during HSC
mobilisationCellular and molecular determinants that regulate osteoblasts at the endosteal niche during HSC
mobilisation
Lay Description (from application):
Treatments for leukaemia (e.g. chemotherapy) severely deplete immune and blood cells from patients.
Transplantation of new blood forming cells (blood stem cells) into these patients is essential, but challenges are
faced with isolating sufficient numbers in ways that preserve their ability to reconstitute the blood post
transplant. My research aims to advance understanding of current methods used to isolate these cells and
ultimately to improve the success of blood stem cell transplantation.
Research achievements (from final report):
Background and rationale: Hematopoetic stem cells (HSC) are essential to the daily replenishment of all cells
in the blood and immune system. The purpose of my research was to improve our understanding of the
interactions between HSC and the cells within the bone marrow (BM) niche where these cells reside.
Mobilisation of HSC from BM to blood is common practice in the clinic for the easy collection of HSC, as
aposed to direct collection of BM from donors. Osteoblasts OB (bone forming cells) are one of the main
components of the HSC endosteal niche in BM. During mobilisation of HSC to OB are completely ablated
from the endosteal niche. Therefore we sought to further define the mechanisms governing this event to better
understand the processes of HSC mobilisation. , Achievements and outcomes:, * Proved that OB are depleted
from the endosteal niche during HSC mobilisation and that this is not mediated by osteoclasts (bone absorbing
cells)., * Identified that stimulating bone formation and inhibiting bone absorbtion can improve mobilisation of
multilineage repopulating or potent HSC. This is a potential method that could be used in conjunction with
mobilisation in the clinic to harvest better quality HSC for transplant., * Generated a molecular signature of the
factors that surround and maintain HSC at the endosteal niche. This identified a myriad of novel targets with
potential involvement in the maintainence of HSC quiesence and self renewal.
Expected future outcomes:
With these studies we have identified a number of novel genes to the field of HSC biology. These genes could
hold the secrets to HSC biology and ultimately provide new drug targets for improved mobilisation of HSC, or
better yet, allow us to identify the factors necessary to farm the most effective repopulating HSC in vitro for the
treatment of malignant hematopoietic diseases.
Name of contact:
Falak Helwani
Email/Phone no. of contact:
falak.helwani@gmail.com
NHMRC Research Achievements - SUMMARY
Grant ID: 566706
Start Year: 2009
CIA Name: A/Pr Nigel Waterhouse
End Year: 2010
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: Career Development
Fellowships
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $88,065
Title of research award:
Investigating mitochondrial outer membrane permeabilization during programmed cell deathInvestigating
mitochondrial outer membrane permeabilization during programmed cell death
Lay Description (from application):
Cancer cells often contain defects which prevent their death. To kill cancer cells we must either reset or bypass
these defects. Release of cytochrome c from mitochondria is a critical event in cell death and proteins that
block this event render cells resistant to many cancer therapies. My research will determine how cytochrome c
release occurs, how this event is regulated and how to kill cancer cells in which cytochrome c release is
blocked.
Research achievements (from final report):
This study continued our investigations into the role of mitochondria in cell death, which was published in Cell
Death and Differentiation. Sedelies et al 2008. In that paper we described a critical role for mitochondria in
cancer cell death by cytotoxic lymphocytes. This resulted in a hypothesis that neutralizing molecules that
protect the mitochondria would re-sensitise cancer cells to cytotoxic lymphocyte induced death. The current
grant allowed us one year to generate preliminary date towards using a novel pan-Bcl-2 inhibitor together with
natural killer cells with defects in the mitochondrial pathway to apoptosis.
Expected future outcomes:
The subsequent findings will be published in early 2012.
Name of contact:
Nigel Waterhouse
Email/Phone no. of contact:
nwaterhouse@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 567086
Start Year: 2009
CIA Name: Dr Katherine Baran
End Year: 2013
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: Early Career Fellowships
(Overseas)
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $162,920
Title of research award:
Is the tumour suppressor activity of p53 independent of its transcriptional role?Is the tumour suppressor
activity of p53 independent of its transcriptional role?
Lay Description (from application):
To become cancerous, a cell must avoid death. As such, cancer cells often contain defects in cell death
pathways which render them resistant to pro-death stimuli, including many chemotherapeutic drugs. To design
new and better cancer therapies, it is essential that we understand the critical molecular processes that control
cell death. This will allow the development of more effective ways to either reset, or bypass, defects in cell
death pathways which have contributed to cancer formation.
Research achievements (from final report):
p53 may mediate apoptosis through a transcription-independent (cytoplasmic) manner by functioning
analagously to the BCL-2 family of proteins. We aimed to identify the molecular mechanisms by which p53
mediates this pro-apoptotic function, and whether this promotes tumor suppression in vivo. We were unable to
clearly demonstrate a role for cytoplasmic p53 in inducing apoptois, and therefore propose that its
transcription-function is the predominant mechanim for tumor suppression. , Therefore, we are currently using
a microarray analysis approach to determine the molecular basis required for p53-mediated tumor suppression.
To date, there is no p53 target-gene knockout mouse strain that recapitulates the dramatic cancer predisposition
of p53 null mice. We are studying mice that lack the proline rich domain (PRD) of p53 (p53dP). This region is
crucial in regulating the stability and expression of p53 and its transcription-dependent function. Cells that
express p53 without its PRD show similar resistance to apoptosis as p53 knockout cells but mice lacking the
PRD are resistant to spontaneous tumor formation, whereas the p53KO mice are not. This suggests that p53dP
maintains a differential response necessary to prevent tumor formation. We will use shRNA library screens to
determine which genes are important for the spontaneous tumor suppression function of p53 in vivo and in
vitro.
Expected future outcomes:
It is becoming more evident that the apoptotic and cell cycle arrest function of p53 may be dispensable for
preventing tumor suppression. Current ideas suggest that metabolic, anti-oxidant and repair functions of p53
may promote tumor suppression. This is the only study to date that uses a microarray approach to identify
exactly what function of p53 is necessary for spontaneous tumor suppression.
Name of contact:
Katherine Baran
Email/Phone no. of contact:
katherine.baran@stjude.org
NHMRC Research Achievements - SUMMARY
Grant ID: 604303
Start Year: 2010
CIA Name: A/Pr Jean-Pierre Levesque
End Year: 2012
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: NHMRC Project Grants
Main RFCD: Haemotology
Total funding: $586,428
Title of research award:
Role of the hypoxia-inducible transcription factor HIF-1a in controlling haematopoietic stem cell fateRole of
the hypoxia-inducible transcription factor HIF-1a in controlling haematopoietic stem cell fate
Lay Description (from application):
Haematopoietic stem cells (HSCs) reside in the bone marrow (BM) and make all immune and blood cells. We
have found that, in the areas of the BM where HSC normally live, the level of oxygen is very low (hypoxia)
and decreases even further when HSC are forced to move into the blood in order to be collected for
transplantation. This project is to better understand how oxygenation of the BM controls HSC behaviour and
properties, and to evaluate its impact on HSC transplantation.
Research achievements (from final report):
This project has been very successful, leading to the publication of 7 research articles, and the submission of an
US patent to protect our discoveries. During this project, we discovered that the oxygen sensing pathway in
blood stem cells is essential to maintain these stem cells in the marrow. Furthermore, we have discovered that
drugs that activate this oxygen-sensing pathway and make cells believe that they are in an environment that
does not contain oxygen, could be clinically useful 1) to protect blood stem cells from accidental irradiation, 2)
to harvest larger numbers of blood stem cell for transplantation, and 3) to enhance their engraftment following
transplantation.These drugs could therefore be used to protect blood stem cells and maintain blood formation in
people that could be exposed to high levels of irradation, and could be used to enhance the success of blood
stem cell mobilisation and tranplantation in cancer and leukaemia patients.
Expected future outcomes:
We are now establishing industry partnership with a US biotechnology company to test several drugs acting on
the oxygen-sensing pathway, to enhance the mobilisation and transplantation of blood stem cells. These studies
will consolidate our patent and test the feasibility of this approach in the clinic to improve the efficacy and
outcome of blood stem cell tranplantation in cancer patients.
Name of contact:
Jean-Pierre Levesque
Email/Phone no. of contact:
jplevesque@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 604306
Start Year: 2010
CIA Name: A/Pr Kristen Radford
End Year: 2012
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: NHMRC Project Grants
Main RFCD: Cellular Immunology
Total funding: $589,545
Title of research award:
TARGETING THE HUMAN CROSS-PRIMING DENDRITIC CELLS FOR
IMMUNOTHERAPYTARGETING THE HUMAN CROSS-PRIMING DENDRITIC CELLS FOR
IMMUNOTHERAPY
Lay Description (from application):
Specialized white blood cells called dendritic cells (DCs) are essential to inducing the immune system to
eradicate cancers and viral infections in mice. We have defined human DC subsets and related their functional
capacities to the mouse DC subsets. We will now identify the human DC subsets involved in the induction of
cancer and viral immune responses and use this information to develop clinical therapeutic cancer vaccination
trials.
Research achievements (from final report):
Special white blood cells called dendritic cells (DCs) can teach the body's own immune response to fight
cancer and have been used as cancer vaccines. These vaccines are safe and can be effective in some patients.
However they are also expensive and require removal of patients' blood to manufacture. Our research focusses
on developing new vaccines to be more effective, cheaper, and more practical to manufacture. Data by
ourselves and others has demonstrated that different subtypes of DCs are responsible for driving different types
of immune responses. During the first year of this project, we published data that identified a rare human DC
subtype (called CD141+ DC) as being the key subytpe for generating immune responses effective at fighting
cancer. A commentary in the prestigious journal, Nature Medicine, described our finding as "a needle in the
'cancer vaccine' haystack". As a result, CD141+ DC are now predicted to be the most relevant targets for the
development of new cancer vaccines. As CD141+ DC are rare and expensive to isolate, we developed and
validated a practical mouse model in which these and other DC subsets develop. We have been using this
model to better understand CD141+ DC function and to evaluate novel vaccine strategies that specifically
target these DC in vivo. We have established proof-of-principle that an antibody that binds specifically to
CD141+ DC can effectively target these cells in vivo and this is now a promising approach to develop further
for cancer vaccines.
Expected future outcomes:
We have established a powerful model to study human DC in vivo. This practical model can now be used to
evaluate new vaccine strategies that target human DC in vivo. A new vaccine that targets CD141+ DC, without
requiring their removal from the patient will be developed for clinical trial.
Name of contact:
Kristen Radford
Email/Phone no. of contact:
kradford@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 614206
Start Year: 2010
CIA Name: A/Pr John Hooper
End Year: 2012
Admin Inst: Mater Medical Research Institute, Brisbane
Grant Type: NHMRC Project Grants
Main RFCD: Endocrinology
Total funding: $582,205
Title of research award:
The role of a protease activated receptor system in prostate cancer bone metastasis.The role of a protease
activated receptor system in prostate cancer bone metastasis.
Lay Description (from application):
Prostate cancer is one of the most significant health issues for men. This disease occurs because certain
proteins start to function abnormally. Our focus is on a protein called PAR2, present on the surface of prostate
cancer cells and bone cells, which we propose helps cancer cells to spread to bone. In our project, we aim to
understand how this happens so that we can develop ways to block prostate cancer metastasis to bone.
Research achievements (from final report):
Prostate cancer preferentially spreads to bone. The mechanisms by which it does this are poorly understood.
We have been examining the role in this process of a cell surface receptor called PAR2. Our data indicate that
blocking the function of PAR2 reduces prostate tumour burden in the skelton of mice. The data also show that
blocking PAR2 in this model reduces adverse effects on bone - there is less of the bone growth that is typical of
prostate cancer bone metastasis in men. Data from experiments using mouse tissue ex vivo suggest that PAR2
is a molecular switch controlling whether precursor cells in the bone become fat cells (adipocytes) or bone
forming cells (osteoblasts). When prostate cancer cells are present they flick this switch so that oseoblast
activity increases. We propose that this represents a key mechanism by wich prostate cancer skeletal metastasis
causes painful bone growth.
Expected future outcomes:
Further study of PAR2 will reveal the mechanisms by which it controls the fate of bone forming and fat
forming cells. It will also reveal how prostate cancer cells disrupt this process. Selective blocking of PAR2
may be a way to reduce the painful growth of bone that accompanies prostate cancer bone metastasis.
Name of contact:
John Hooper
Email/Phone no. of contact:
jhooper@mmri.mater.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 201700
CIA Name: Dr Joseph Sasadeusz
Admin Inst: Melbourne Health
Main RFCD: Infectious Diseases
Total funding: $135,770
Start Year: 2002
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Studies of HIV and HBV co-infection.Studies of HIV and HBV co-infection.
Lay Description (from application):
There are a number of patients throughout Victoria that are co-infected with both hepatitis B virus (HBV) and
human immunodeficiency virus (HIV). These patients are currently being treated for HIV with multiple
antiviral drugs and are living for longer periods. Lamivudine is one of the drugs in the HIV antiviral treatment
regime. This antiviral is also effective against hepatitis B virus and is the only licensed nucleoside analogue
that is used in the treatment of hepatitis. The aim of this project is to investigate the liver disease caused by
HBV in co-infected patients and the development of antiviral resistance due to the long-term treatment with
lamivudine. We will develop a data base to monitor virological, biochemical and histological parameters for
each of these co-infected patients. We will collate all information on these patients that are attending these
various centres. This data base will be essential for monitoring the disease in patients with a poor immune
system versus patients with a normal immune system. The HBV virus isolated from these patients will be
characterised by sequence analysis. The sequence analysis of these viruses will be compared before and after
treatment to determine any resistance markers that have developed. These resistant markers will be copied into
an infectious clone using specialised molecular techniques. Clones containing these resistant markers will be
analysed in the laboratory to determine the antiviral sensitivity to lamivudine and a number of new drugs
against hepatitis B virus. This information will be important in treating patients that are co-infected with HBV
and HIV and have already developed resistance to lamivudine.
Research achievements (from final report):
This data has now been translated into a multinational collaborative 5-year program sponsored by the United
States National Institutes of Health (NIH) which will prospectively evaluate the natural history of HIV and
HBV coinfected individuals to determine the natural history of liver disease in this patient population. It will
specifically determine the resistance profile over time of various HBV active antiviral agents in coinfected
patients as well as evaluating hepatotoxicity of antiretroviral therapies in this patient population.
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 332502
CIA Name: Dr David Curtis
Admin Inst: Melbourne Health
Main RFCD: Haematology
Total funding: $422,600
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of red blood cell and platelet formation by bHLH proteinsRegulation of red blood cell and platelet
formation by bHLH proteins
Lay Description (from application):
Continuous production of normal blood cells by the bone marrow is a process critical to human life. Disruption
of this process leads to diseases such as leukemia, aplastic anemia and myelodysplasia which have devastating
consequences for affected patients. Pivotal to understanding these diseases is a knowledge of the regulation
of normal blood production. Our laboratory works on a gene known as SCL that is critical for blood formation.
We have recently shown that loss of SCL in adult bone marrow leads to abnormalities in two types of blood
cells, the red blood cells and the platelets. This grant will extend this important observation to understand how
the production of these cells is altered and what is its consequence. Our studies will help clarify the basis of
blood cell formation and may impact on how we diagnose and treat a wide variety of blood disorders.
Research achievements (from final report):
This research award has generated a genetically modified mouse strain that has allowed us to study the role of a
gene called SCL in the blood system of the adult. We have shown that while SCL is essential for the
development of stem cells of the blood, it is not required for the maintence of these stem cells during adult life.
In adult stem cells it is important for determining the type of cells that blood stem cells can generate.
Specifically, SCL is required for the production of platelets, especially during times of stress such as after
chemotherapy, and is required to prevent the formation of mast cells, a cell type that mediates allergic
conditions such as asthma, food and drug allergies. These findings suggest that tagetting this gene could be
useful for controlling the production of platelets or mast cells.
Expected future outcomes:
This work will lead to a better understanding of how the body regulates blood cell production from stem cells.
Name of contact:
David Curtis
Email/Phone no. of contact:
dcurtis@wehi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 997002
CIA Name: Dr David Curtis
Admin Inst: Melbourne Health
Main RFCD: Cellular Immunology
Total funding: $318,136
Start Year: 1999
End Year: 2004
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
Charecterisations pf the receptor tyrosine kinase, NYK on early haemopoietic progenitorsCharecterisations pf
the receptor tyrosine kinase, NYK on early haemopoietic progenitors
Lay Description (from application):
Not Available
Research achievements (from final report):
Understanding the genetic control of stem cells will lead to new methods of growing blood stem cells in the
laboratory, and regulating the type of cells that cen be made from blood stem cells.
Expected future outcomes:
Understanding the genetic control of stem cells will lead to new methods of growing blood stem cells in the
laboratory, and regulating the type of cells that cen be made from blood stem cells.
Name of contact:
Dr David Curtis
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 257501
CIA Name: Prof Simon Foote
Admin Inst: Menzies Research Institute
Main RFCD: Not Allocated
Total funding: $4,134,917
Start Year: 2003
End Year: 2007
Grant Type: Programs
Title of research award:
Genetic Anaylsis of complex disease processesGenetic Anaylsis of complex disease processes
Lay Description (from application):
The genome project has opened the path for the study of diseases using genetics. This approach is still quite
recent in human and mammalian biology. It requires a large amount of input from statisticians and computer
scientists as well as from the biologists and clinicians working on the disease. The team is looking for genes
causing complex genetic diseases and use human populations and families as well as mouse models of human
diseases. This includes modifiers of cancer development and response to infectious disease as well as deafness
and autoimmune diseases.
Research achievements (from final report):
This program resulted in the development of new techniques that are being used in the analysis of microarray
chips. This technology is revolutionising biology with its ability to garner a holistic view of transcription
within a cell or tissue. However it results in the production of huge amounts of data. This program has
produced many approaches to the analysis of this data. The genetics side of the program has resulted in the
identification for genes for epilepsy, leishmaniasis and the analysis of the genetics of malarial infection. The
studies into the genetics of multiple sclerosis and DNA methylation enhance our understanding of MS and
tumourigenesis.
Expected future outcomes:
We expect to continue to supply approaches to the analysis of genomic data and to work towards the
identification of genes for genetic diseases.
Name of contact:
Professor Simon Foote
Email/Phone no. of contact:
simon.foote@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 403002
CIA Name: A/Pr Alison Venn
Admin Inst: Menzies Research Institute
Main RFCD: Epidemiology
Total funding: $89,050
Start Year: 2006
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Exposure to high dose estrogens in adolescence: long term effects on mammographic breast densityExposure to
high dose estrogens in adolescence: long term effects on mammographic breast density
Lay Description (from application):
Breast density is a well established risk factor for breast cancer, and has been shown to be reversibly influenced
by hormone exposures in adult life. As one of the important roles of sex hormones during puberty is mammary
cell proliferation, it is plausible that exposures at this earlier life stage might have a sustained influence on
breast tissue composition and density, and subsequent breast cancer risk. This project aims to increase our
understanding of the influence of sex hormones in adolescence on breast cancer risk by testing the hypothesis
that exposure to large doses of sex hormones during adolescence has long-term effects on mammographic
density. This will be done by comparing the mammographic densities of women who were treated with high
doses of estrogen for tall stature during adolescence with women who were similarly assessed for tall stature
but not treated. No previous study in humans has examined the long-term effects on breast tissue of high dose
estrogen exposure at this early life stage. This is not surprising, given the difficulty in finding a suitable
exposed population. This cohort of women, assessed or treated for tall stature, provides us with a unique
opportunity to examine these influences. This research will add to our understanding of the influence of sex
hormones in adolescence on mammographic density and breast cancer risk. If hormonal factors in adolescence
are shown to influence mammographic density, this may lead to new avenues for breast cancer prevention
efforts that are targeted much earlier in life. This information may lead to new research directions examining
adolescent hormonal exposures (both endogenous and exogenous) and their influence on breast tissue.
Research achievements (from final report):
This project aims to increase our understanding of the influence of sex hormones in adolescence on breast
cancer risk by testing the hypothesis that exposure to large doses of estrogen with progesterone during
adolescence has long-term effects on mammographic breast density, a measurement taken from breast x-rays
and known to be a determinant of breast cancer risk. The aimed to compare the mammographic densities of
women aged 40 years and over who were treated with sex hormones for tall stature during adolescence, with
those of women who were similarly assessed for tall stature but not treated., In total, 336 women (70.9% of
those eligible) agreed to participate in the study by completing a telephone interview and having a
mammogram or allowing us to access mammograms they had already had. Interviews have been completed
and mammograms are being collected from BreastScreen services across Australia for scanning and the
subsequent measurement of breast density. It is anticipated that the results will be available in late 2007.
Expected future outcomes:
This research will add to our understanding of the influence of sex hormones in adolescence on mammographic
density and breast cancer risk. If hormonal factors in adolescence are shown to influence mammographic
density, this may lead to new avenues for breast cancer prevention efforts and research directions that are
targeted much earlier in life.
Name of contact:
Helen Jordan
Email/Phone no. of contact:
hljordan@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490014
Start Year: 2008
CIA Name: Dr Adele Holloway
End Year: 2011
Admin Inst: Menzies Research Institute
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $521,961
Title of research award:
How does basal chromatic structure predict cytokine gene responses?How does basal chromatic structure
predict cytokine gene responses?
Lay Description (from application):
To recognise foreign pathogens and eradicate them from the body, immune cells need to quickly switch on
genes encoding factors which communicate between cells and drive the immune response. Incorrect expression
of these genes contributes to immune diseases such as asthma, arthritis and leukaemia. The aim of this project
is to study how the DNA environment of immune genes controls their ability to be switched on and off, and
how altering this environment leads to incorrect gene expression.
Research achievements (from final report):
To recognise foreign pathogens and eradicate them from the body, immune cells need to quickly switch on
genes encoding factors which communicate between cells and drive the immune response. Incorrect expression
of these genes contributes to immune diseases such as asthma, arthritis and leukaemia. , This research
investigated the DNA environment of one of these immune genes (called GM-CSF) to determine how this
environment controls the ability of the gene to be switched on and off. The research identified DNA-associated
factors that control the ability of the gene to respond to immune signals. Further, the study found that there is a
set of immune genes that have similar DNA environments in immune cells to the GM-CSF gene and this
allows them to respond to immune signals in a similar way. These genes have a particular DNA environment
which maintains them in a tightly repressed state in the absence of an immune signal. Finally the study found
that changes to the DNA environment of the GM-CSF gene occur in leukaemic cells, and that this contributes
to the dysregulated activity of the gene in these cells. These findings are significant because unlike changes to
the DNA sequence, changes to the DNA environment are reversible with pharmacological agents, and therefore
suggests a potential avenue for therapeutic intervention in disease states in which these immune genes are
aberrantly expressed.
Expected future outcomes:
Expected future outcomes are a better understanding of how DNA environment controls the response of genes
to immune signals, and how changes to these environments contribute to immune diseases.
Name of contact:
Dr Adele Holloway
Email/Phone no. of contact:
a.f.holloway@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436013
Start Year: 2007
CIA Name: Dr John Condon
End Year: 2008
Admin Inst: Menzies School of Health Research Grant Type: NHMRC Project Grants
Main RFCD: Preventive Medicine
Total funding: $489,707
Title of research award:
An epidemic of vulvar cancer in young women: investigating the role of Human Papillomavirus and genetic
susceptibilityAn epidemic of vulvar cancer in young women: investigating the role of Human Papillomavirus
and genetic susceptibility
Lay Description (from application):
Vulvar cancer is a rare disease; in 1993-1997 the age-adjusted incidence rate in Australia was 1.4 per 100,000
women (average 207 cases per year), similar to the incidence in most other countries. An epidemic of cases of
vulvar cancer has been identified in younger Indigenous women living in remote communities in the Northern
Territory (NT). Vulvar cancer is over fifty times more common in women aged less than 50 years in these
communities than in the total Australian population. Women in these communities also experience higher rates
of high-grade Vulvar Intraepithelial Neoplasia (a pre-cursor to vulvar cancer), than elsewhere in the NT.
Vulvar cancer is usually much more common in older women than younger women. In young women vulvar
cancer and VIN are thought to be caused by infection with cancer causing strains of human papillomavirus
(HPV), particularly the strain known as HPV16. In older women, vulvar cancer is not caused by HPV. In the
remote communities in the NT, vulvar cancer is occurring almost entirely in young women, the amount of
cancer occurring in older women in these communities is similar to the amount expected in the total Australian
population. This project will investigate the cause of this epidemic of vulvar cancer and high-grade VIN. It
will investigate whether HPV16 is more prevalent in these communities than elsewhere in Australia; whether
there is a variant strain of HPV16 in these communites that is more virulent at causing cancer, and whether the
disease occurs more commonly in families, which would mean that women in these communities inherit an
increased susceptibility to vulvar cancer and VIN. This project will help to increase our understanding of
vulvar cancer and VIN, help to control this epidemic, and inform whether the new HPV vaccines may be
effective in preventing vulvar cancer in these communities.
Research achievements (from final report):
We examined whether the very high incidence of vulvar cancer amongst Aboriginal women in the Arnhem
Land area was due to: (a) an unusual (virulent) strain of oncogenic human papillomavirus (HPV) type 16; or
(b) a higher community prevalence of infection with oncogenic HPV genotypes., Sixty one stored specimens of
vulvar cancer and vulvar intraepithelial neoplasia (a cancer precursor) in the Northern Territory (NT) were
assessed. We found no differences in the amount or type of HPV infection in specimens from Arnhem Land
compared with other NT regions, and we identified a strain of HPV 16 that is common worldwide., Our survey
of HPV infection in Arnhem Land involved offering 562 Aboriginal woman a 'women's health check' which
included cervical and vulvar/vaginal/perianal samples taken for HPV genotyping. We found the prevalence of
oncogenic HPV in the cervix was similar to what has been reported in other Australian women. The prevalence
in the vulvar/vaginal/perianal area was higher than in the cervix, and higher than what has been reported in
previous studies examining the concordance of infection at various genital sites, but this excess was not
sufficient to explain the much higher incidence of vulvar cancer. We believe this is the largest study of HPV
infection amongst Aboriginal women in remote communities. The findings indicate that the high incidence of
this cancer in Arnhem Land is not due to an unusual strain or a very high community prevalence of HPV
infection, indicating that other possible environmental or genetic factors may be involved.
Expected future outcomes:
This study will continue to inform a control strategy to prevent this disease, which is currently focused on HPV
vaccination and early detection of lesions in routine pap screening and antenatal care. Future work will
examine why the prevalence of vulvar/vaginal/perianal infection is much higher than that previously reported.
Name of contact:
NHMRC Research Achievements - SUMMARY
John Condon
Email/Phone no. of contact:
john.condon@menzies.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436014
Start Year: 2007
CIA Name: A/Pr John Condon
End Year: 2011
Admin Inst: Menzies School of Health Research Grant Type: NHMRC Project Grants
Main RFCD: Indigenous Health
Total funding: $412,354
Title of research award:
Health system performance and outcomes for Indigenous Australians with cancer: a national study.Health
system performance and outcomes for Indigenous Australians with cancer: a national study.
Lay Description (from application):
Cancer has only recently been recognised as a significant Indigenous health issue, partly because no national
information has been available on the impact of cancer on Indigenous people or on health system performance
for Indigenous cancer patients. Recent research in the Northern Territory has demonstrated large deficiencies in
diagnosis, treatment and survival for Indigenous compared to other cancer patients. Despite imperfect data on
Indigenous status, important information can be obtained about health system performance for Indigenous
Australians from national administrative databases and registers. This project will assess health system
performance and outcome for Indigenous people with cancer at a national level for the first time. It will
compare Indigenous with non-Indigenous cancer survival rates for Australia as a whole, including regional
(urban/rural/remote) variations and time trends. For those states where data on stage at diagnosis and hospital
treatment are available, it will also investigate the performance of diagnostic and treatment services for
Indigenous cancer patients by comparing their stage at diagnosis and surgical treatment with that for nonIndigenous patients. Time trends for each of these issues will be examined using data from those states with
data of adequate quality and consistency over the past 10-15 years. This project will provide the
methodological basis for regular reporting of Indigenous cancer survival and related statistics in the national
cancer reporting system and demonstrate that national monitoring of the acute care system for Indigenous
people is possible for other conditions. The results of this research will directly inform acute care policy and
practice for Indigenous people with cancer (particularly the relative need for improvement in primary health or
acute care services), and have implications for the performance of the acute care system system more generally
for Indigenous Australians.
Research achievements (from final report):
This project has assessed the data quality of cancer registrations data for Indigenous (Aboriginal and Torres
Strait Islander) Australians and published reliable semi-national cancer incidence statistics, including
urban/remote comparisons, for Indigenous Australians for the first time, covering NSW, NT, Qld and WA
combined (84% of the Indigenous population). The project is investigating cancer survival for Indigenous
compared with other Australians, including geographical variation and (for breast cancer only) the role of late
diagnosis (i.e. more advanced disease at the time of diagnosis) in causing lower cancer survival of Indigenous
women; this work has not yet been completed. The project has developed and validated methods that can now
be used for regular reporting of national cancer incidence statistics for Indigenous Australians by national
health statistics agencies, and will do the same for cancer survival statistics when that component of the project
is complete., So far the project has: published an invited review of cancer in Indigenous Australians in Lancet
Oncology; published a paper on data quality and cancer incidence for Indigenous Australians; completed
methodological comparison and validation of cause-specific compared with relative survival analysis and
recommended that cause-specific survival analysis be used for calculating survival rates for Indigenous cancer
patients rather than the usual relative survival method; and supported Ms Kalinda Griffiths's successful
completion of an Indigenous cancer epidemiology traineeship; she was the Northern Territory Young
Australian of the Year for 2011, in some part based on her research work, and is now undertaking a PhD in
cancer epidemiology.
Expected future outcomes:
Regular reporting of national cancer incidence and survival statistics for Indigenous Australians, using the
methods developed by this research, will increase the focus of the Australian health system on improving
preventive programs (eg, cervical screening, tobacco control) and cancer treatment for Indigenous Australians.
NHMRC Research Achievements - SUMMARY
Name of contact:
John Condon
Email/Phone no. of contact:
john.condon@menzies.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490344
Start Year: 2008
CIA Name: Ms Rachel McMahon
End Year: 2013
Admin Inst: Menzies School of Health Research Grant Type: SRDC - Research
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $42,750
Title of research award:
Case conferencing, quality of life and palliative care for clients from remote communities in the Northern
TerritoryCase conferencing, quality of life and palliative care for clients from remote communities in the
Northern Territory
Lay Description (from application):
This project addresses an area in the delivery of palliative care in rural and remote Top End of the NT, where
research is seriously lacking. It will focus on the relationship between quality of life and communication
between health providers and palliative clients and their carers. The conduit of communication will be case
conferences and family conferences. There has been some research that reflects that case conferencing (in
urban areas) in palliative care leads to improved quality of life (Mitchell 2006). This project will be assessing
whether there is a similar association between quality of life and case conferencing in rural and remote
Northern Territory. The project will also assess the dynamics of communication between palliative clients and
their carers and the health providers.
Research achievements (from final report):
This research project began by trying to explore how quality of life at the end of life may be maximised by
communication between remote Top End palliative care patients and palliative care health professionals. The
original proposed method of communication to examine between remote palliative care clients and health
professionals was case conferencing. In the early stages of the research, it was found that case conferencing
could be classified as structured interviewing. The project supervisor had completed research on an
individualised quality of life measurement tool, SEIQoL-DW, finding it to be a useful form of interviewing
which allowed the individual to direct their own care in accordance to providing the best quality of life.
However, the palliative care team felt strongly that the SEIQoL-DW tool was culturally inappropriate. They
were extremely protective of their clients, including in how to best provide care. This research found that the
health professionals thought that all care and communication with remote Indigneous palliative care clients was
absolutely sacred. This project had stumbled across a subculture of protection from the health professionals,
where they had become gate keepers of the remote palliative care clients, revering the clients and protecting
their sacredness. Any attempts to measure quality of life at the end of life such as via SEIQoL-DW, were
deemed by palliative care staff to be culturally inappropriate. Unstrucutured interviews between health
professionals and clients were found to be the most effective, culturally appropriate and least offensive form of
communication.
Expected future outcomes:
This research raises the issue of culturally appropriate communication between remote palliative care staff and
their clients. Further research in culturally appropriate communication with remote palliative care clients needs
to be addressed, eg along the lines of Sharing the True Stories.
Name of contact:
Rachael Mcmahon
Email/Phone no. of contact:
rachael.mcmahon@menzies.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 552414
Start Year: 2009
CIA Name: A/Pr Patricia Valery
End Year: 2012
Admin Inst: Menzies School of Health Research Grant Type: NHMRC Project Grants
Main RFCD: Indigenous Health
Total funding: $701,662
Title of research award:
Closing the Divide: Aboriginal and Torres Straight Islander People and Cancer SurvivorshipClosing the
Divide: Aboriginal and Torres Straight Islander People and Cancer Survivorship
Lay Description (from application):
This project will significantly contribute to Indigenous health research through addressing the current
knowledge gap about the unmet support needs of Indigenous cancer patients in Queensland. This study will
also investigate if the existing cancer supportive care is adequate for Indigenous patients and how an
indigenious patient navigator will adress the barriers to accessing existing care. Indigenous research capacity
building is a strong element of this project.
Research achievements (from final report):
This is the first study to provide comprehensive information on the type and prevalence of unmet supportive
care needs (SCN) in Australian Indigenous cancer patients. We included in the study over 250 Indigenous
cancer patients from four hospitals in Queensland. Psychosocial and practical assistance were particularly
important for Indigenous cancer survivors. The most commonly reported SCN items where patients reported
'moderate-to-high need for help with' included: 'money worries', 'worrying about the illness spreading', 'feeling
down or sad', 'anxiety', and 'worry about results of treatment'.We conducted 3 months follow-ups with over 200
of patients recruited, and 6 months follow-ups with about 160 patients. Preliminary analysis showed that at 6
months post-diagnosis 53% had at least one 'moderate to high' level unmet need, 33% reported 'no need' for
help. The main reason for loss to follow-up being death.We also worked collaboratively with Qld Health to
pilot the role of an Indigenous Patient Navigator in addressing the needs of Indigenous cancer patients
receiving treatment at the Cairns Base Hospital. The Navigator was widely accepted and welcomed,
successfully assessed patients' needs, and attempted to address them. Understanding unmet needs is critical for
planning supportive care that is responsive to the specific needs of Indigenous cancer survivors.
Expected future outcomes:
Our findings will inform service provision on how to best facilitate a multidisciplinary supportive care
approach for Indigenous people from an Indigenous perspective, and ultimately leading to urgently needed
improvements in the health of the increasing numbers of Indigenous Australians with cancer.
Name of contact:
Patricia Valery
Email/Phone no. of contact:
patricia.valery@menzies.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1003817
Start Year: 2011
CIA Name: A/Pr John Condon
End Year: 2013
Admin Inst: Menzies School of Health Research Grant Type: NHMRC Project Grants
Main RFCD: Aboriginal and Torres Strait Islander Health
Total funding: $711,841
Title of research award:
A vulvar cancer cluster in young Indigenous women in Arnhem Land: investigation of community knowledge,
genetic susceptibility and supportive care responseA vulvar cancer cluster in young Indigenous women in
Arnhem Land: investigation of community knowledge, genetic susceptibility and supportive care response
Lay Description (from application):
Cancer of the vulva is 50 times more common in young Aboriginal women in Arnhem Land than in other
women. Human Papillomavirus (HPV), which also causes cervical cancer, is the usual cause of this cancer;
initial investigations have found that HPV is present in these cancers but is not the reason for the excessive
incidence. This study will investigate local knowledge about this disease, and whether inherited susceptibility
or an environmental cancer-causing substance are the cause of the excess.
Research achievements (from final report):
The research finding from this project have directly informed health policy and practice in the remote
Aboriginal communities of Arnhem Land, with respect to Well Women's Screening, HPV vaccination and
outreach gynaecology monitoring of at-risk individuals. By identifying the psychosocial aspects of vulvar
cancer diagnosis and treatment, we have contributed to discourse surrounding the experiences of cancer
patients within the health care system, and have highlighted the particular challenges of those who live in
remote regions. The genetic arm of this project found clear evidence of a genetic susceptibility to vulvar cancer
in this population, and identified a gene that may be responsible that is currently being followed up with
sequencing and functional studies.
Expected future outcomes:
This work will continue to inform the public health response to the vulvar cancer cluster in Arnhem Land.
Further elucidation of the role of genetic risk factors in vulvar cancer will have important implications for
understanding the aetiology and biology of vulvar cancer in the wider community.
Name of contact:
A/Prof John Condon
Email/Phone no. of contact:
john.condon@menzies.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1004643
Start Year: 2011
CIA Name: A/Pr Patricia Valery
End Year: 2013
Admin Inst: Menzies School of Health Research Grant Type: NHMRC Project Grants
Main RFCD: Aboriginal and Torres Strait Islander Health
Total funding: $691,814
Title of research award:
A comparative study: Patterns of Care, Comorbidities and Quality of Life of Indigenous and non-Indigenous
people with lung, head &amp; neck, breast or gynaecological cancersA comparative study: Patterns of Care,
Comorbidities and Quality of Life of Indigenous and non-Indigenous people with lung, head &amp; neck,
breast or gynaecological cancers
Lay Description (from application):
Indigenous people with cancer have higher mortality rates and poorer survival than other Australians. Cancer
treatment is complex, involves many therapies; there are many opportunities for someone to become ‘lost’ in
the system, causing unnecessary morbidity and personal distress. This study will compare the treatment and
management of Indigenous cancer patients against ‘best practice’ guidelines with the aim of identifying factors
that are modifiable (i.e. health services, treatment patterns).
Research achievements (from final report):
Understanding the treatment trajectory of Indigenous patients must be investigated in order to improve their
outcomes. Overall (for all cancers), we showed that Indigenous people had more advanced cancer stage, more
comorbidities and received less cancer treatment, factors which contribute to poorer cancer survival. Moreover,
for patients with a more favourable distribution of such prognostic factors, Indigenous patients received less
treatment overall relative to non-Indigenous patients. When we investigated specific cancers we found some
differences. Indigenous women with breast cancer had serious comorbidity and more advanced disease than
non-Indigenous women. There was no difference in the histological types of tumours, the proportions of
oestrogen and progesterone receptor positive tumours, in time from diagnosis to treatment, treatment
completion rates, mode of treatment, or rates of tamoxifen use between groups. Indigenous patients diagnosed
with colorectal cancer were not more likely to have comorbidity, advanced disease at diagnosis or less
treatment than non-Indigenous people; they had similar all-cause or cancer survival. We also found that cancer
services in Queensland are located where there are relatively low percentages of Indigenous people compared
with the whole population, and very few were classed 'Indigenous-friendly'., Results of our work substantially
added to the limited information available on the patterns of care of Indigenous cancer patients.
Expected future outcomes:
Understanding the treatment trajectory of Indigenous cancer patients must be investigated in order to improve
their outcomes. Results of our work substantially added to the limited information available. The transfer of
knowledge about coordination of care to policy and practice will ultimately lead to improvements in the health
of the increasing numbers of Indigenous people with cancer.
Name of contact:
Patricia Valery
Email/Phone no. of contact:
patricia.valery@menzies.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 124331
CIA Name: Prof Peter Rogers
Admin Inst: Monash University
Main RFCD: Obstetrics and Gynaecology
Total funding: $759,928
Start Year: 2000
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Endometrial angiogenesisEndometrial angiogenesis
Lay Description (from application):
The lining of the uterus is unusual compared to other parts of the adult body in that new blood vessels grow
and then breakdown during menstruation every month. The aim of this project is to understand what controls
the growth and regression of these uterine blood vessels. This information is of immediate relevance to a
number of clinical problems where an ability to either promote or prevent blood vessel growth would be of
major advantage. For example, increased blood vessel growth would accelerate wound healing, while blocking
blood vessel growth would prevent the growth and spread of cancers. Another disorder that could be
controlled through preventing blood vessel growth is endometriosis, a disease where cells from the lining of
the uterus grow inside the abdomen causing pain and infertility. Endometriosis affects upto 10% of women.
Research achievements (from final report):
The primary focus of this research project was to better understand how new blood vessels form in the lining of
the uterus. A fundamental knowledge of uterine blood vessel growth is relevant to a large number of common
women's health problems, including endometriosis, menorrhagia (excessive menstrual blood loss),
breakthrough bleeding (irregular menstrual bleeding associated with hormone replacement therapy and
hormonal contraceptives), endometrial cancer, fibroids, infertility and establishment of a normal placenta
during pregnancy.
Expected future outcomes:
This project has increased fundamental knowledge that underpins our understanding of uterine function in both
normal and diseased states. Future work will build on this knowledge base to develop better treatments and
outcomes for a number of diseases that affect the uterus, including endometriosis, endometrial cancer, fibroids
and inadequate placental function.
Name of contact:
Peter A W Rogers
Email/Phone no. of contact:
Peter.rogers@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143540
CIA Name: Prof Christina Mitchell
Admin Inst: Monash University
Main RFCD: Enzymes
Total funding: $408,055
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Characterization of 72 and 52 kDa inositol polyphosphate 5-phosphatases: role in vesicular trafficking and cell
deathCharacterization of 72 and 52 kDa inositol polyphosphate 5-phosphatases: role in vesicular trafficking
and cell death
Lay Description (from application):
Cells respond to the external environment, stress, hormones and grow th factors by generating messages inside
the cell that send a signal to the nucleus that stimulates cell growth. One such signalling network is that
produced by membrane lipids known as phosphoinositides. Enzymes or kinases that modify these membrane
lipids in particular an enzyme known as the PI 3-kinase generate potent signalling molecules that regulate cell
growth. It has been shown by many studies that signals generated by the PI 3-kinase are amplified in certain
human cancers. Inherited cancer syndromes have been described in which the cell has lost the ability to switch
off these lipid messenger molecules. The current project aims to investigate two recently identified enzymes
called 5-phosphases that have the ability to terminate PI 3-kinase membrane signals. Both these enzymes were
isolated and characterized by the host laboratory and it is predicted they will play distinct roles in the cell. The
72 kDa 5-phosphatase is predicted to regulate protein and vesicular trafficking to the surface of cell. This
proposal aims to investigate if the 72 kDa 5-phosphatase can regulate the intracellular sorting of new proteins
within the cell. We have also noted the 72 kDa 5-phosphatase may play a role in the development of the
nervous system in particular the ability of nerves to send branches out and differentiate. This proposal will
investigate this hypothesis. The second enzyme that we have isolated is a 52 kDa 5-phosphatase. This enzyme
is present in many cells. We have compelling evidence that the enzyme forms a complex with a recently
decribed protein called SODD that stops cells from dying in response to inappropropirate signals. We predict
the 52 kDa 5-phosphatase may function to prevent prolonged cell survival as is observed in cancer. We will
investigate if this enzyme regulates the cell death pathway and if increased or decreased levels of the 52 kDa 5phosphatase alter cell survival
Research achievements (from final report):
Cells respond to hormones, stress, growth factors and other environmental stimuli resulting in secretion, cell
growth, cell division and other specialized functions. These cellular responses are dependent on the generation
of intracellular signals that send messages either to the nucleus, the cytoskeleton or membrane compartments
and thereby elicit a specific response. A specific subset of signalling molecules that are localized on membrane
compartments are called phosphoinositides. We have indentified two new enzymes that regulate the uptake of
glucose into the cell and therefore may play a major role in diabetes. The new enzyme the 72 kDa 5phosphatase enhances the movement of the glucose into the cell, without a requirement for insulin. Therefore
this new enzyme may help in preventing insulin resistant diabetes by enhancing glucose uptake. We have
investigated the molecular mechanisms by which the 72 kDa enzyme promotes glucose uptake, predominantly
into fat cells and have shown that the enzyme generates a new signal called PtdIns 3-P. This latter signal
stimulates the transport of small carrier protein called Glut-4 from inside the cell to the cell surface which in
turn can then mediate glucose uptake.
Expected future outcomes:
The discovery of this new signalling pathway that regulates glucose uptake into the cell play in the future lead
to new mechanisms to treat insulin resistant diabetes and bypass a requirement for insulin.
Name of contact:
Christina Mitchell
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
christina.mitchell@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143541
Start Year: 2001
CIA Name: Prof Christina Mitchell
End Year: 2003
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $423,564
Title of research award:
Characterization of a novel family of LIM-only proteins; role in skeletal muscle
differentiation.Characterization of a novel family of LIM-only proteins; role in skeletal muscle differentiation.
Lay Description (from application):
This project aims to study the role of a new family of related proteins in skeletal muscle. One of these proteins
has been shown to be deficient in muscle cancers. These proteins are important for the development and normal
functioning of muscle. Related proteins have been shown to be linked with heart failure in animals. These
proteins also potentially interact with proteins causing muscular dystrophy. We have identified a new family
of proteins in skeletal muscle. These proteins contain so-called LIM domains, which mediate binding to other
proteins. This study proposes to determine how these proteins influence skeletal muscle development and the
consequences of abnormal levels of these proteins. This may lead to insights into the mechanism of cardiac
failure, muscle cancers and muscular dystrophy.
Research achievements (from final report):
This grant has examined the role of a family of muscle proteins called FHL proteins and how they regulate
both heart and peripheral skeletal muscle function. Inherited muscle disorders of the heart and peripheral
muscle include cardiomyopathies and muscular dystrophies that cause significant muscle weakness and in
some cases early death, due to respiratory failure or muscle weakness. We have identified a new family of
proteins - the FHL proteins that may play a major role in both inherited and acquired muscle diseases. We have
shown that the FHL proteins if overexpressed disrupt muscle function and lead to a form of muscle
hypertrophy. This is of significance given others have identified that a family member FHL1 is highly
expressed in some conditions associated with cardiac hypertrophy. We have identified a potential mechanism
by which FHL-1 may cause such muscle enlargement, which despite an increase in muscle size the muscle is
actually weakened. We have shown the FHL1 protein forms a complex with a structural protein called myosin
binding protein C, which itself binds myosin, a protein critical to muscle function. We have demonstrated
FHL1 expression regulates myosin binding protein C activity. This is of significance given myosin binding
protein C is mutated in a significant number of inherited diseases associated with cardiac abnormalities leading
to cardiac death, in particular in young adults.
Expected future outcomes:
These studies should lead to further understanding of the molecular mechanisms leading to inherited and
acquired heart disease which may lead to novel therapies.
Name of contact:
Christina Mitchell
Email/Phone no. of contact:
christina.mitchell@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143615
CIA Name: A/Pr Robert Medcalf
Admin Inst: Monash University
Main RFCD: Gene Expression
Total funding: $241,528
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Post transcriptional regulation of the plasminogen activator inhibitor type 2 genePost transcriptional regulation
of the plasminogen activator inhibitor type 2 gene
Lay Description (from application):
The process of wound healing, removal of blood clots, cell migration and the metastatic spread of cancers
requires the recruitment of specialised proteases. These proteases act primarily to degrade other proteins,
mainly in the extracellular space, which in turn allow cells to move around, wounds to close, and blood clots to
disappear. The plasminogen activating system is one of the most important enzyme systems involved in these
events. One of the proteases that cleaves plasminogen to its active form, plasmin, is urokinase (u-PA).
Plasminogen activator inhibitor type 2 (PAI-2) is a serine protease inhibitor that inhibits u-PA activity. The
degree of u-PA activity therefore depends on the relative levels of u-PA and PAI-2. In addition to controlling
u-PA activity, PAI-2 also influences intracellular events including cell proliferation, differentiation and
apoptosis. PAI-2 protein and mRNA levels are substantially modulated by many cytokines and growth factors.
This project addresses the molecular mechanisms underlying the regulation of PAI-2 gene expression. We have
recently shown that a significant degree of PAI-2 regulation occurs at the level of PAI-2 mRNA stability, and
we have identified two regions within the PAI-2 mRNA that play a role in this process. Both regions provide
binding sites for cellular proteins. We have identified one of these binding proteins to be HuR, a protein that
has recently been shown to control the stability of other mRNAs. The specific aims of this project are firstly, to
determine the role of HuR in the control of PAI-2 mRNA stability, and secondly, to clone a characterise the
other PAI-2 mRNA binding proteins we have identifed. An understanding of how cells modulate levels of
PAI-2 mRNA will significantly add to the broader field of gene regulation and may also provide new clues to
influence PAI-2 levels in the body.
Research achievements (from final report):
The plasminogen activator inhibitor type 2 (PAI-2) gene encodes for an inhibitor of a protease called
urokinase. Urokinase is involved in the spread of cancer and the presence of PAI-2 limits the activity of
urokinase. PAI-2 is therefore able to limit cancer spreading via inhibiting urokinase. The basic aim of the
project was to determine how this protease inhibitor is regulated in cells. PAI-2 is subject to posttranscriptional regulation and we have shown that the longevity of the PAI-2 transcript is strongly influenced
by sequences located within the 3'-untranslated region (3'-UTR). We had previously identified HuR as a
protein that binds to the mRNA instability element in the 3'-UTR. One of the aims of this project was to
identify and characterise additional proteins that associate with this instability element in the 3'-UTR. This was
successful as we identified by genetic means, a cytoplasmic protein called tristetraprolin (TTP) as an important
protein that binds to the instability element in the 3'-UTR and results in PAI-2 mRNA turnover. We are
currently seeing how HuR and TTP interact in the regulation of PAI-2 mRNA turnover. We also identified and
characterised an instability element within exon 4 of the PAI-2 coding region and demonstrated that this region
provides a binding site for proteins with a molecular weight of 52-54 kD. , Although PAI-2 inhibits urokinase
which is an extracellular protease, PAI-2 exists predominantly intracellularly. During the course of this project,
we also assessed the functional role of PAI-2 in monocytes. Using THP-1 cells that cannot express PAI-2, we
stably expressed either wild-type or mutant variants of PAI-2 into these cells. We demonstrated that PAI-2
caused in a significant decrease in the proliferation rate of the THP-1 cells and also altered the ability of these
cells to differentiate in response to phorbol ester. Hence, a novel role for PAI-2 has been identified.
Expected future outcomes:
It is expected that we will be able to better understand the role of TTP in the regulation of PAI-2 mRNA
turnover, and how it is involved with HuR and other factors that influence PAI-2 mRNA instability. We also
expect to reveal novel intracellular targets for PAI-2 that are involved in cell proliferation.
NHMRC Research Achievements - SUMMARY
Name of contact:
Robert Medcalf
Email/Phone no. of contact:
robert.medcalf@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143674
CIA Name: Dr BERNADETTE SCOTT
Admin Inst: Monash University
Main RFCD: Tumour Immunology
Total funding: $453,055
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Role of CD4 T cells and APCs in the induction and maintenance of an effective antitumor responseRole of
CD4 T cells and APCs in the induction and maintenance of an effective antitumor response
Lay Description (from application):
Many cancers are still untreatable by conventional therapies (surgery, chemotherapy and radiation). This
includes malignant mesothelioma, a cancer associated with previous exposure to asbestos. Exposure can occur
up to 30 years before the onset of this disease. The average time of survival for patients, from the time of
diagnosis, is about nine months and the incidence of this disease is increasing. Novel therapies are therefore
required to help alleviate this disease and perhaps eradicate it. Immunotherapy - using the body's own defence
system to help fight cancer- is one potential form of new treatment. However we need to understand how the
immune system and cancer normally interact with one another if we are to make rational decisions about the
design of immunotherapies. We have established a laboratory model which allows us to investigate this
interaction. We will determine which components of the immune system are required to eradicate cancer and
at which stages of cancer growth they are most important. By understanding these pieces of the puzzle we may
be able to "tweak" the system more appropriately or design vaccines that will be effective in "at risk"
populations.
Research achievements (from final report):
Tumor antigen presentation is not directly via tumor-T cell interaction but rather through T cell-APC
interactions. The use of chemotherapeutics for induction of tumor apoptosis can enhance this presentation.,
Phenotyping of the antigen presenting cells within the tumor: Macrophages are the most prominent, infiltrating
cell in the established tumor comprising approximately 50% of the tumor mass. In the, established tumor these
macrophages, defined by the surface expression of the common, macrophage marker F4/80, are predominantly
MHC class II negative. They also express markers, associated with the metalophillic macrophages of the
spleen. The loss of the MHC class II, expression is a kinetic event -early during tumor growth, infiltrating
macrophages express class II., However by about day 14 post-tumor inoculation, the macrophages are
predominantly class II, negative. This time point coincides with the time at which adoptive becomes totally
ineffective.;, These macrophages also make IL-10, the neutralisation of which in vivo, also modulated, tumor
growth .Depletion of macrophages, using liposomes containing a cytotoxic drug, leads to tumor regression
Expected future outcomes:
To further the macrophage depletion work to determine whether it is suitable for translation to clinical studies
ie does it work with established tumors as would present in a clinic.
Name of contact:
Error! Bookmark not defined.
Email/Phone no. of contact:
bernadette.scott@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143710
Start Year: 2001
CIA Name: Prof David Jans
End Year: 2005
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $650,383
Title of research award:
Regulation of nuclear import of viral oncoproteins and transcription factors by protein-protein
interactionsRegulation of nuclear import of viral oncoproteins and transcription factors by protein-protein
interactions
Lay Description (from application):
The present application examines the controls that exerted over proteins that localize in the nucleus of
eukaryotic cells. This relates relates integrally to cellular processes such as growth, development and
oncogenesis. This research area is not represented elsewhere in Australia, and the particular experimental
strategies to approach the problem, revolving around the use of special quantitative microscopic techniques are
novel internationally. One part of the application seeks to examine transport within the cell of complexes of
interacting proteins, rather than single proteins, under as close as possible to physiologically relevant
conditions. This will be truly unique, and of great importance to our comprehension of eukaryotic cell function.
This application examines particular types of negative control over protein nuclear localization. Since many
proteins show such regulation, and in particular important proteins controlling cell growth and division, the
results are fundamentally important to our understanding of how cells function in general. Further, this
understanding may be applied in disease situations, such as viral-mediated oncogenesis. In the work we
propose to do, viral proteins with functions relating to cancer will be examined in detail, as well as a cellular
protein which is recognised by them - the tumor suppressor Rb. We intend to examine several viral
oncoproteins which target Rb; one is a protein (E7) from the Human Papilloma Virus which has been
frequently associated with cervical carcinomas and other cancers. Accordingly, the results may have direct
application to viral-induced cancer, and our work may lead to understanding of the regulation of protein
transport to the nucleus. This may thus afford a new approach at the pharmacological level to combat
transformation.
Research achievements (from final report):
Our work has established new mechanisms of regulation of viral gene products by phosphorylation as well as
mechanisms of nuclear import of tumor suppressor molecules. We have established that many viral gene
products of interest traffic between the nucleus and cytoplasm at very specific time points during infection, and
that this can be critical to the virus infectious cycle. We have mapped the targeting sequences, nuclear transport
receptors, and phosphorylation sites for simian virus SV40 large tumor antigen (T-ag), human cytomegalovirus
(hCMV) processivity factot ppUL44, Dengue virus RNA polymerase NS5, chicken anemia virus (CAV) viral
protein 3and respiratory syncitial virus (RSV) matrix (M) protein. We have additionally made progress in
understanding of nuclear import of the human immunodeficiency virus HIV-1 preintegration complex (PIC),
through increased understanding of the unique nuclear import mechanisms of the PIC components Vpr, MA,
and integrase. Understanding the mechanisms of nuclear import of viral gene products may enable new antiviral therpeutic approaches to be developed., In terms of tumor suppressors, we have established that they
possess a unique property in terms of nuclear import, whereby microtubule integrity plays a key role to "fast
track" Rb (retinoblastoma susceptibility factor) and p53 to the nucleus. Understanding of mechanisms
regulating nuclear import of anti-cancer proteins may enable new approaches to control transformation.
Expected future outcomes:
Understanding of the nuclear transport mechanisms of critical viral gene products and their regulation will
enable novel drug target to be identified for the development of new antiviral therapeutics. Understanding the
trafficking mechanisms of tumor suppressors enables new insight into oncogenesis, and may lead to new
approaches to tackle cancer.
Name of contact:
NHMRC Research Achievements - SUMMARY
D. Jans
Email/Phone no. of contact:
David.Jans@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143872
CIA Name: Dr Simone Schoenwaelder
Admin Inst: Monash University
Main RFCD: Haematology
Total funding: $312,981
Start Year: 2001
End Year: 2004
Grant Type: Career Development Fellowships
Title of research award:
Investigate the role of the small RHoA in platelet functionInvestigate the role of the small RHoA in platelet
function
Lay Description (from application):
Not Available
Research achievements (from final report):
In the event of blood vessel injury, platelets elicit a series of responses that must be tightly regulated on a
number of levels. They must ensure the formation a thrombus that is of sufficient size to seal off the damaged
area, preventing blood loss, whilst not disrupting blood flow to vital organs by causing vessel occlusion.
Unfortunately, the consequences of disrupted platelet regulation are seen all too frequently in the clinical
setting, with the incidence of cardiovascular related diseases such as DVT, heart attack and stroke, remaining
some of the major causes of morbidity and mortality in the western world today. Therefore, it is pertinent to
gain a comprehensive understanding of the platelet-facilitated mechanisms regulating vessel wall maintenance.
Studies durign this funding period have focussed on examination of the major platelet receptor Integrin aIIbb3,
as it is critical in the physiological process of haemostasis and is also implicated in pathological thrombosis.
The adhesive properties of this integrin must be tightly regulated so as to prevent inappropriate platelet
interactions in the absence of vessel injury, but at the same time allow rapid up regulation of integrin affinity
upon vessel injury, in order to allow thrombus growth and prevent blood loss. Our studies suggesting distinct
yet cooperative roles for a family of enzymes, the Ras family members Rap1b and RhoA, in regulating integrin
aIIbb3 adhesive function. Ultimately, characterisation of the role of these small GTPases, and their relevant
regulatory molecules, including PI3 -kinase, may provide important insight into the key regulators of platelet
integrin function, and may offer novel insight into potential therapeutic targets with which to manipulate
platelet function.
Expected future outcomes:
By identifying the key enzymes and signalling pathways regulating aspects of platelet function, we hope to
utilise this knowledge to provide better strategies for drug design to combat thrombosis.
Name of contact:
Simone Schoenwaelder
Email/Phone no. of contact:
Simone.Schoenwaelder@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145784
CIA Name: Prof PETER GIBSON
Admin Inst: Monash University
Main RFCD: Gastroenterology
Total funding: $196,528
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Elucidation of mechanisms by which fibre promotes or protects from colorectal tumorigenesisElucidation of
mechanisms by which fibre promotes or protects from colorectal tumorigenesis
Lay Description (from application):
In a carefully controlled animal model of colon cancer development, dietary fibre can increase or decrease the
likelihood of colon cancer development. It depends upon the type of fibre being fed to the animal. The
mechanisms by which fibres can increase or decrease the likelihood of colon cancer developing are, however,
poorly understood. In this proposal, we will attempt to elucidate at least some of the mechanisms. We plan to
define whether animals consuming fibres that increase cancer development have factors in their faeces that
affect the health of the cells that line the colon (the ones that form the cancers). This will be examined in both
the test tube and in healthy rats. Whether fibres influence the access of these factors to the lining cells by
"sequestering" or hiding the factors in the jelly-like consistency some fibres produce in the colon will also be
examined. The results will help identify conditions in the faeces that alter the susceptibility of colons to
developing cancer. By identifying these conditions, we can then apply our knowledge to human subjects, so
that we might be able to identify those at a higher or lower risk of developing colon cancer and we can advise
and (subsequently prove) ways of modifying diet to reduce the risk of colon cancer.
Research achievements (from final report):
Using a rat model of the development of cancer of the colon, we have directly shown that, under physiological
conditions, the product of fermentation of fibre, butyrate, and the physical effects that fibre induces in the colon
are independent mechanisms by which fibnre protects from colon cancer. We also have demonstrated that the
amount of butyrate exposed to the lining of large bowel has to be large - equivalent of that produced by high
fibre intake. Fibre does not influence cancer develoment by chanign the noumber of "styem cells" in the large
bowel. In ulcerative colitis, a condition that has an increased risk of colon cancer, the bowel responds
abnormally to fibre, with altered metabolism of it by bacteria and altered speed by which it proples thorugh the
bowel. The signficance of these findings is that, if fibre is to influence the devlopment of bowel cancer, it needs
to be given in large amounts (as has not been done in clinical trials) and that we cannot necessarily extend
findings in the normal situation to disease states where bowel cancer might be increased.
Expected future outcomes:
An increased understanding of the large bowel and how its content interact with dietary components will be
gained from future studies derived from the current findings.
Name of contact:
Peter Gibson
Email/Phone no. of contact:
Peter.Gibson@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 194205
Start Year: 2002
CIA Name: Dr Simone Schoenwaelder
End Year: 2004
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $226,320
Title of research award:
Elucidation of signalling enzymes regulating the small GTPase RhoAElucidation of signalling enzymes
regulating the small GTPase RhoA
Lay Description (from application):
Many normal and pathological processes in the human body depend on the ability of cells to attach to a
biological surface (adhesion), spread out, or move to another site (migration). Examples of biological processes
that require such events include the division and arrangement of cells in a developing embryo, or the ability of
cancer cells to spread (metastasise). A driving force behind the attachment or movement of cells is their ability
to rearrange a scaffolding called the cytoskeleton. The cytoskeleton is similar to the skeleton of the human
body, in that it acts to maintain cell shape and rigidity. However, it is also actively reorganised to participate in
many cellular processes, including cell attachment and movement. By furthering our understanding of how the
cytoskeleton is rearranged, this will provide important insights not only into the basics of cell behaviour, but
will also have important implications for a number of human disease states. This proposal aims to investigate
mechanisms that regulate the reorganisation of the cytoskeleton. It is well established that the rearrangement of
this scaffolding, in many different types of cells, is controlled by a family of proteins called the Rho family of
small GTPases. One of the members of this family, RhoA, has a specific role in controlling cell attachment,
and interestingly, has been implicated in the invasive and metastatic properties of human tumour cells. We
have recently identified a protein that is responsible for controlling the activation of RhoA. This proposal aims
to further our understanding of how this protein regulates RhoA, and therefore cell attachment and movement.
Given that cell attachment and movement are important events contributing to the spread of tumours, this study
may provide important insight into alternative approaches of controlling cell movement, and ultimately
malignant progression.
Research achievements (from final report):
Many normal and pathological processes in the human body depend on the ability of cells to attach to a
biological surface (adhesion), spread out, or move to another side (migration). Examples of biological
processes that require such events include the adhesion of blood cells, known as platelets, to areas of blood
vessel injury, in order to prevent blood loss. A driving force behind the attachment or movement of cells is
their ability to rearrange a scaffolding called the cytoskeleton. The cytoskeleton is similar to the skeleton of the
human body, in that it acts to maintain cell shape and rigidity. However, it is also actively reorganised to
participate in many cellular processes, including cell attachment and movement, be rearranging cell membrane
and surface receptors. By furthering our understanding of how the cytoskeleton is rearranged, and the
attachment proteins it modulates, this will provide important insights not only into the basics of cell behavior,
but will also have important implications for a number of human disease states., , We have investigated the role
of a family of proteins known as Ras family GTPases, in the regulation of the platelet cytoskeleton and
adhesive function. We have found strong evidence that a member of the Rho family, RhoA, may regulate an
important attachment protein, or receptor, called intefrin alphaIIbbeta3, which is modulated by cytoskeletal
reorganisation, and is critical for platelet adhesion. Our results demonstrate that inhibition of RhoA can reduce
the ability of platelets to be able to stick to injured blood vessels under blood flow conditions. It is hoped that
further studies will delineate the mechanisms utilised by RhoA and other Ras family members and potentially
identify new targets for therapeutic intervention.
Expected future outcomes:
We hope to further examine whether RhoA or other Ras family members may act as targets that we can
manipulate to modify platelet adhesion.
Name of contact:
NHMRC Research Achievements - SUMMARY
Simone Schoenwaelder
Email/Phone no. of contact:
Simone.Schoenwaelder@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 194330
Start Year: 2002
CIA Name: Dr James Whisstock
End Year: 2004
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $421,320
Title of research award:
A bioinformatic analysis and structural study on the inositol polyphosphate 5-phosphatasesA bioinformatic
analysis and structural study on the inositol polyphosphate 5-phosphatases
Lay Description (from application):
Communication (or signaling) inside the cell enables the cell to respond to factors in its external environment,
such as hormones or growth factors. The inositol phosphates and the phosphoinositides are signaling
molecules that play an essential role in intracellular communication. The 5-phosphatases are able to modify
these molecules and terminate, and in certain cases stimulate, signals. Failure to properly control intracellular
signaling pathways may result in abnormal cell growth and cancer. Human 5-phosphatases are a complex
family of enzymes: In addition to the region responsible for phosphatase activity (the catalytic domain) many
members contain other protein "modules" . These associated domains may perform critical roles, such as
regulating intracellular location and docking with other proteins. This project aims to perform a computational
investigation of human 5-phosphatases and their associated domains. In particular we will search for novel
phosphatases, investigate the evolutionary relationships between members of each domain family, and make
testable predictions regarding the function of uncharacterized domains. This study will take advantage of data
produced by the recently completed human genome project. The second aim of the project is to determine,
using X-ray crystallography, the three-dimensional shape (or atomic structure) of a representative member of
the 5-phosphatase family. Solving the structure of a 5-phosphatase at the atomic level is critical for
understanding the nature of substrate specificity and for rational drug design.
Research achievements (from final report):
The research focuses on an important family of human signalling enzymes, the inositol 4- and 5-phosphatases.
These proteins are involved in numerous disease processes including diabetes and cancer. We have conducted a
extensive computational investigation in regards to the distribution, phylogeny and putative function of the 4and 5-phosphatases. In addition we have investigated the context of the catalytic domain of these enzymes, and
identified several novel signalling modules. In the second part of the project, we have made extensive progress
towards crystallising a human 5-phosphatase. The latter aspect of the work is an essential step towards
understanding the precise 3-D structure and specificity of human 5-phosphatases.
Expected future outcomes:
We aim to determine the 3-Dimensional structure of a human 5- and 4-phosphatase - these data will provide
invaulable insight into the mechanism of function and dysfunction of these proteins.
Name of contact:
James Whisstock
Email/Phone no. of contact:
James.Whisstock@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 194404
Start Year: 2002
CIA Name: Prof Christina Mitchell
End Year: 2004
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $406,980
Title of research award:
The regulation of PI 3-kinase second messenger molecules, PtdIns(3,4)P2 and PtdIns 3-P.The regulation of PI
3-kinase second messenger molecules, PtdIns(3,4)P2 and PtdIns 3-P.
Lay Description (from application):
Cells respond to the external environment, hormones, and growth factors by generating messages inside the
cell that send a signal to the nucleus that stimulates cell growth. One such signalling network is that produced
by membrane lipids known as phosphoinositides. Enzymes that produce these signals are known as kinases.
There has been considerable interest in the PI 3-kinase as the signals generated by this enzyme are increased in
many human cancers. Inherited cancer syndromes have been described that have lost the ability to switch off PI
3-kinase signals. The current project aims to investigate a recently identified enzyme called the 4-phosphatase
that has the ability to terminate PI 3-kinase signals. Recent studies have shown this enzyme regulates cell
growth. In addition key experiments have shown the enzyme is important as it may regulate certain strains of
bacterial infection. This research proposal aims to investigate how the enzyme works to regulate these growth
promoting signals. This may help us develop novel therapeutic strategies to control cell growth.
Research achievements (from final report):
We have characterised a new enzyme that may play a significant role in neuronal development. This enzyme
functions to terminate specific membrane localized signals in cells, called phosphoinositides, which function to
regulate cell proliferation and death. We have determined the intracellular localization and catalytic activity of
the enzyme and have demonstrated the enzyme designated the 4-phosphatase is localised to a specific
intracellular compartment known as the endosome. Recent studies have identified the 4-phosphatase may
represent a novel tumour suppressor protein that prevents cancer formation. Gene targetted deletion of the 4phosphatase in mice results in early neonatal death from neuronal dysfunction, and failure to thrive. In addition
our studies have indicated 4-phosphatase deficient mice demonstrate significant abnormalities of the blood
system, specifically a small spleen and thymus. We are currently investigating how the 4-phosphatase functions
in regulating neuronal development and blood function.
Expected future outcomes:
Our studies we demonstrate the role this novel signal terminating enzyme plays in regulating cell proliferation,
neuronal and blood development and the role the enzyme plays in preventing specific human cancers.
Name of contact:
Christina Mitchell
Email/Phone no. of contact:
christina.mitchell@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 215219
CIA Name: Prof Andrew Elefanty
Admin Inst: Monash University
Main RFCD: Haematology
Total funding: $295,500
Start Year: 2002
End Year: 2004
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
I became interested in the control of mesodermal patterning in mammalian cells, in order to discover the genes
acting 'upstream' of the haematopoietic regulator gene, SCL, that I had studied previously. Because homeobox
genes of the Mix family played such a role in the frog, I embarked upon a project to clone its mammalian
counterparts. I cloned murine and human Mix genes (Mixl1), studied their expression and completed a
'knockout' of the mouse Mixl1 gene. These studies indicated that Mixl1 was expressed in the primitive streak
of the mammalian embryo, a transient structure from which mesoderm and endoderm derive. Mixl1 was
required for normal development of these germ layers., A major interest of my laboratory has been in the
regulation and directed differentiation of embryonic stem cells towards haematopoietic and pancreatic
endocrine lineages. We created mouse ES cell lines in which the Green Fluorescent Protein (GFP) reporter was
inserted into the Mixl1 locus, enabling us to monitor the appearance of mesodermal and endodermal precursors
during ES cell differentiation. We utilised a serum freee culture system that permitted the screening of growth
factors regulating early mesendodermal differentiation. We expanded the GFP reporter system to generate
additional mouse ES cells in which GFP was inserted into the locus of the pancreatic regulator gene, Pdx1.
Studies with this cell line have enabled us to devise rational protocols for the differentiation of ES cells
towardes pancreatic insulin producing beta cells., More recently, we have worked with human ES cells,
transferring the expertise that we have developed from the mouse to the human systems. We have developed an
improved method for the serum free, growth factor directed differentiation of human ES cells towards
mesodermal lineages that has enabled us to efficiently generate human haematopoietic cells.
Expected future outcomes:
We are generating human ES cells with gene specific reporters and we are transferring the pancreatic
differentiation protocols to human ES cells. We will improve the efficiency and the quantities of the human ES
derived blood cells that we are generating.
Name of contact:
Andrew Elefanty
Email/Phone no. of contact:
andrew.elefanty@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219279
CIA Name: Prof Susan Davis
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $2,000,000
Start Year: 2003
End Year: 2007
Grant Type: Centre of Clinical Excellence
Title of research award:
The Clinicial Centre of Research Excellence at the Jean Hailes Foundation: for the study of women's
HealthThe Clinicial Centre of Research Excellence at the Jean Hailes Foundation: for the study of women's
Health
Lay Description (from application):
The major health issues affecting women from the mid-reproductive years include depression, disorders of
mood and sexual function, and breast cancer, with cardiovascular disease, osteoporosis, and osteoarthritis
becoming increasingly prevalent with age. Linking each of these are their known or probable causal
associations with oestrogens and androgens. This Centre will provide an opportunity for comprehensive and
multidisciplinary research into the role of oestrogens and androgens in these disorders.
Research achievements (from final report):
Work conducted within this CCRE grant has demonstrated normal levels for androgens in women by age and
shown that blood androgen levels are not useful for predicting female sexual function nor are they determinants
of wellbeing. However we have also demonstrated that low serum DHEA is associated with lower sexual
function and that higher blood DHEA levels are associated with some specific areas of greater cognitive
performance. We have demonstrated that androgens do not contribute to differences in cardiovascular disease
risk markers, namely lipids and C reative protein, and that in women aged 40-67 years, levels of endogenous
testosterone and adrenal pre-androgens do not appear to make a contribution to the volume of the medial or
lateral tibial cartilage measured by MRI. We have reconfirmed that the capacity of adipose tissue to produce
estrogen seems to increase significantly with age and to be unaltered by exogenous estrogen therapy. This
difference in extragonadal estrogen production with age may play a pivotal role in the increase in estrogendependent malignancies in the postmenopausal years. The CCRE provided seed funding for the establishment
of a large longitudinal study of the health and wellbeing of women newly diagnosed with breast cancer, which
is ongoing, and a randomised controlled trial of the efficacy and safety of DHEA in women with low libido.
Expected future outcomes:
This research has contributed fundamental knowledge and understanding of the role of androgens in women
with findings from this research directing future studies in this field. Furthermore, the longitudinal study of the
consequences of breast cancer will be an ongoing source of information in this important women's health area.
Name of contact:
Prof Susan Davis
Email/Phone no. of contact:
susan.davis@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 234707
CIA Name: A/Pr Martin Lackmann
Admin Inst: Monash University
Main RFCD: Oncology and Carcinogenesis
Total funding: $490,500
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Development and evaluation of biological reagents targeting and inhibiting function of the EphA3 receptor on
tumor cellsDevelopment and evaluation of biological reagents targeting and inhibiting function of the EphA3
receptor on tumor cells
Lay Description (from application):
Eph receptors and their ligands regulate morphogenesis in the embryo; they direct migration and positioning of
cells during the formation of tissue layers and organ systems. There is little evidence for a function of Ephs in
adult tissues. However, their abundant, un-scheduled occurrence in various malignant tumours, indicates a
role in cancer. Human EphA3, the principle subject of this proposal, is not found in adult tissue but is present at
high levels in lung, kidney and brain tumours, leukemia and malignant melanoma. High levels of EphA3 and
corresponding ligands correlate with melanoma progression, and EphA3 stimulation triggers repulsion and
detachment of melanoma cells. It is likely that Eph A3 is involved in release and spreading of tumour cells
during melanoma progression. We have characterised reagents, the soluble EphA3 ligand and a monoclonal
anti-EphA3 antibody, which bind EphA3 with high affinity and specificity. We will use these two proteins, or
modified forms containing attached radiochemicals or cytotoxins, to target human tumours that were implanted
into into immuno-deficient mice as animal model system. Our studies will determine if the specificity of our
reagents, suggested from previous in-vitro studies, will allow imaging of EphA3 containing tumours, and effect
their targeted killing. We will also use a tissue culture model, containing artificial epidermal and dermal layers
of skin cells, to study if an inhibitory form of the EphA3 ligand will affect the invasiveness of EphA3 positive,
metastatic melanoma cells. Furthermore, we will identify essential parts of this ligand to develop inhibitors
with improved pharmacological properties. Together, our studies will establish the role for EphA3 in cancer
progression and to assess the efficacy of EphA3 targeting for tumor killing and prevention of metastasis. We
envision that this will provide the groundwork for Eph-specific reagents with anti-metastatic action in cancer
therapy.
Research achievements (from final report):
Previously we characterised a cell surface molecule present on cancer cells, human EphA3, that is rarely found
in healthy adult organs and tissues, but is present at high levels in lung, kidney and brain tumours, leukemia
and malignant melanoma. The more recent research supported by this grant confirmed EphA3 as potential
molecular target for anti-cancer therapy, as pronounced expression was observed in several solid tumours as
well as in the tumour vasculature. As basis for therapeutics development we characterised a monoclonal
antibody against EphA3, which alone or in combination with a soluble form of the EphA3 ligand effectively
targets to EphA3-positive human tumours in experimental mice. These lead compounds were IP-protected in a
patent application and recently attracted funding to assess their potential tumour targeting drugs, resulting in a
R&D collaboration with a BioPharma partner to develop EphA3-based anticancer therapeutics.
Expected future outcomes:
Our research forms the basis for the development of a monoclonal antibody-based therapy to treat a variety of
aggressive human cancers. Current development of the antibody therapeutics and a survey of clinical samples
to define suitable patient population, if successful, will allow Phase-1 trials in Australia in 2008.
Name of contact:
Martin Lackmann
Email/Phone no. of contact:
Martin.Lackmann@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 234712
CIA Name: A/Pr Martin Lackmann
Admin Inst: Monash University
Main RFCD: Oncology and Carcinogenesis
Total funding: $200,000
Start Year: 2003
End Year: 2004
Grant Type: NHMRC Development Grants
Title of research award:
Development of anti-metastatic and tumour targeting reagents by design of inhibitors to specific Eph/ephrin
cell-cellDevelopment of anti-metastatic and tumour targeting reagents by design of inhibitors to specific
Eph/ephrin cell-cell
Lay Description (from application):
Metastatic disease, malignant melanoma in particular, is a health issue of considerable global importance with
1,000 fatal melanoma cases/ year in Australia alone. While progress has been made on prevention and early
diagnosis, no curative treatment exists for stage IV melanoma. Tumour progression and the acquisition of
metastatic competence primarily reflect dysregulation of cell adhesion and cell motility rather than
proliferation and survival. In this context, Eph receptor tyrosine kinases (Ephs) and their membrane-bound
ephrin ligands are crucial mediators of cell adhesion and motility and are notably overexpressed in metastatic
tumours rather than primary (benign) lesions5. Our laboratories were the first to identify EphA3 7, and one of
the first to isolate its ligand, ephrin-A5. EphA3 was isolated from acute lymphoblastoid leukemia and
malignant melanoma patients, where increasing expression levels correlate with metastatic progression.
Soluble, non-clustered forms of Ephs and ephrins are effective inhibitors of Eph activity 3 and provide
opportunities to generate specific drugs for cancer therapy. We now propose a research and development
program for the development of EphA3-specific drugs and their production for pre-clinical and clinical
evaluation for placement onto a national and international market.
Research achievements (from final report):
During the progression of human cancers, tumour cells increasingly loose the ability to communicate and to coexist in a regulated fashion with normal cells. Their spreading into surrounding tissue or distant parts of the
body or tumour metastasis is the final stage of many cancers that currently has no treatment options. In our
translational research program we have assessed in pre-clinical models two proteins that target one of these
cell-communication molecules, the EphA3 receptor tyrosine kinase. EphA3 is a cell surface protein directing
cell positioning, including that of tumour cells. We found in human/mouse tumour models that radioactivelytagged conjugates of these potentially therapeutic reagents, a monoclonal antibody (MAb) 'IIIA4' against
EphA3 and the soluble form of the EphA3 ligand ephrin-A5, specifically target transplanted human tumours. In
addition, we found that IIIA4 and ephrin-A5 bind to closely adjacent molecular surfaces and that their
simultaneous binding triggers amplified signalling and dramatically accelerated internalisation of
EphA3/ephrin-A5/IIIA4 complexes. These findings suggest the design of a novel fusion protein with the
combined functionalities of IIIA4 and ephrin-A5, as targeting protein with unsurpassed avidity and specificity
for EphA3.
Expected future outcomes:
By refining in continuing studies the tumour targeting and killing properties of these agents, we are pursuing
the design and production of optimised, second generation reagents with improved pharmacokinetic and
therapeutic potential. This improvement of functional properties will enhance their IP value and our negotiation
position for support of clinical trials.
Name of contact:
Martin Lackmann
Email/Phone no. of contact:
Martin.Lackmann@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236812
CIA Name: Prof Donald McNaughton
Admin Inst: Monash University
Main RFCD: Obstetrics and Gynaecology
Total funding: $291,600
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Infrared spectroscopic imaging in the diagnosis of cervical cancerInfrared spectroscopic imaging in the
diagnosis of cervical cancer
Lay Description (from application):
In Victoria alone around 500000 Pap smears a year are examined for evidence of cancer of the cervix or
conditions that may lead to cancer. This is a time consuming, labour intensive and costly process with a
relatively high failure rate. A number of alternative techniques have been explored in the last decade with a
view to providing a diagnostic technique that is free of human error, more reliable than the Pap method and
easily used. An alternative technique based on using infrared light to probe smears shows promise in providing
such an easily automated reliable method. We, and others have spent a number of years exploring this
technique and have solved a number of the problems associated with it. Based on our work in the field and the
work of others we now wish to develop a methodology using an infrared micro-imaging spectrometer
combined with multivariate statistics that can be used to diagnose cervical cancer and the conditions that lead
to cervical cancer.
Research achievements (from final report):
Infrared images of a number of sections of normal and abnormal cervical tissue samples have been recorded.
From these images profiles typical of the constituent cells and disease states have been extracted to provide a
database. This data is being used to develop computer models capable of determining cell types and disease
states in tissue. Similar work on cervical smears is being carried out to determine whether the computer models
will allow for diagnosis of disease also in cervical smears. This work has the potential to provide a test for
cervical cancer that is cheaper and more reliable than the current Pap test.
Expected future outcomes:
A neural network for diagnosis of cervical disease will be fully developed.
Name of contact:
Don Mcnaughton
Email/Phone no. of contact:
don.mcnaughton@sci.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236870
Start Year: 2003
CIA Name: A/Pr Tony Tiganis
End Year: 2005
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $455,250
Title of research award:
Regulation and function of the protein tyrosine phosphatase TCPTP in mitosisRegulation and function of the
protein tyrosine phosphatase TCPTP in mitosis
Lay Description (from application):
The cell cycle is a universal process by which cells reproduce and it underlies the growth and development of
all living organisms. The most important events of the cell cycle concern the replication of chromosomal DNA
during S phase and the separation of replicated DNA into progeny cells at mitosis. Mitosis is morphologically
the most dynamic phase of the cell cycle and involves the precise coordination of many processes that are
governed by reversible protein phosphorylation. Protein phosphatases play an important role in reversible
protein phosphorylation and they are essential for mitosis. This grant proposal is focused on understanding the
regulation and function of protein phosphatases in mitosis. Our studies will provide novel insight into
processes mediating mitosis and may lead to the development of alternative strategies for treating cancer.
Research achievements (from final report):
In order for an organism to grow and develop, the cells that make up the tissues and organs need to undergo a
process of cellular division, wherein individual cells grow and then divide into two cells. During this process of
cellular growth and division the entire genome needs to be replicated and divided equally into the two daughter
cells. Specific and intricate mechanisms exist to ensure that division occurs in timely and precise manner and
that the DNA is accurately replicated and segregated. Our studies have elucidated a novel process for the
control of cellular division and provide new insights into mechanisms by which tumours may grow.
Expected future outcomes:
N/A
Name of contact:
Tony Tiganis
Email/Phone no. of contact:
Tony.Tiganis@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 237042
Start Year: 2003
CIA Name: Dr Mirella Dottori
End Year: 2004
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $166,048
Title of research award:
Molecular characterisation of human embryonic and carcinoma stem cellsMolecular characterisation of human
embryonic and carcinoma stem cells
Lay Description (from application):
Not Available
Research achievements (from final report):
Stem cell therapy has recently taken a major step forward with the possibility of using human embryonic stem
(ES) cells. The nervous system is a good candidate for stem cell therapy since there are well-established and
efficient protocols for inducing neuronal differentiation from human ES cells. Dr Dottori's research is to study
the differentiation of human ES cells towards specific neural lineages of the central and peripheral nervous
system. Dr Dottori's approach is to analyse genes known to be important during neuronal development of other
species, such as mouse and chick, and investigate their possible role in differentiation of human ES cells,
particularly towards neuronal lineages. Her research has characterized the neuronal cell types that may be
derived from human ES cells, under defined culture conditions. This work is very important for investigating
clinical application of human ES cells for treatment of disorders of the nervous system. Human ES cell biology
is a relatively new field of research and, for both ethical and scientific reasons, there are many technical
challenges that need to be addressed to pursue the research. Through Dr Dottori's research, one of these
challenges was met by establishing appropriate culture conditions and experimental parameters to genetically
modify human ES cells. This will be very useful for future studies in all areas of human ES cell biology.
Expected future outcomes:
Future studies evolving from Dr Dottori's research is to investigate the development of neurons from human ES
cells and the role certain genes may have in this process.
Name of contact:
Mirella Dottori
Email/Phone no. of contact:
mirella.dottori@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284273
CIA Name: Prof Christina Mitchell
Admin Inst: Monash University
Main RFCD: Enzymes
Total funding: $454,050
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Characterization of the 72 kDa inositol polyphosphate 5-phosphataseCharacterization of the 72 kDa inositol
polyphosphate 5-phosphatase
Lay Description (from application):
Cells respond to external signals and the enviroment to undergo cell growth, secretion and or other specialized
functions including control of cell death and or cell size. We have identified a new enzyme (72 kDa 5phosphatase) which resides inside the cell, which we have evidence plays a role in regulating both the
movement of intracellular vesicles and also lipid signals stimulated by insulin. We have characterised the
phospholipids that the enzyme cleaves and demonstrated the generation of new cell signals at specific
subcellular localizations on intracellular membranes. We predict the generation of these specific lipid signals
may play a significant role in controlling the transport of intracellular cargo to specific sites in the cell. In this
grant proposal we aim to examine the regulation of specialised cargo called the glucose transporter, which is
found in fat and muscle cells, and also the mannose 6-phosphate receptor, which regulates the trafficking of
specific enzymes which mediate digestion of proteins. These studies include the clarification of which
phospholipid signals the enzyme terminates and where in the cell this occurs. Secondly, we will examine the
movement of the glucose transporter GLUT-4 in unstimulated cells and in response to insulin and furthermore
how expression of the novel enzyme regulates its movement. We will also examine the movement of the
mannose 6-phosphate receptor and the specific phospholipid signals which control the route the receptor
traffics, using inhibitors of lipid signals and expression of lipid phosphatases and kinases. We will also
examine how our novel enzyme forms complexes with other molecules in the cell and characterise these novel
molecules using basic biochemical assessment of enzyme activity and function. Finally we will examine the
regulation of intracellular messages by our novel enzyme following insulin stimulation, which facilitates
glucose uptake into the cell.
Research achievements (from final report):
Phagocytosis is a biological process where specialised immune cells (macrophages) take up and remove
harmful particles such as bacteria or tumour cells from the circulation. We have shown a novel enzyme the 72
kDa 5-phosphatase is expressed in macrophages and plays a role in regulating phagocytosis and inhibiting the
uptake of particles and bacteria by macrophages. In addition we have shown this enzyme is also present in fat
cells where it may function to regulate glucose metabolism. In addition we have demonstrated that the 72 kDa
5-phosphatase regulates cancer cell proliferation and cell migration.
Expected future outcomes:
Future outcomes will characterise the molecular basis for the regulation of glucose metabolism and
macrophage function by this novel enzyme, the 72 kDa 5-phosphatase
Name of contact:
Christina MitchellEmail/Phone no. of contact:
christina.mitchell@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284344
CIA Name: Dr Caroline Gargett
Admin Inst: Monash University
Main RFCD: Obstetrics and Gynaecology
Total funding: $409,575
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Identification and characterisation of cells with high proliferative potential in human
endometriumIdentification and characterisation of cells with high proliferative potential in human
endometrium
Lay Description (from application):
Each month when the uterine lining does not receive an implanting embryo, this lining is shed as part of the
menstrual process. It is rapidly replaced with a new functional lining that grows from the basal layer that
remains. In post menopausal women, who only have the thin basal layer of the uterine lining, there is rapid
regeneration of the lining when they commence hormone replacement therapy. Despite this remarkable
regenerative capacity of the uterine lining, nothing is known about the precursor cells responsible for its
cyclical growth. Our preliminary studies have shown that the human uterine lining contains a rare population of
cells with high proliferative capacity. This project will identify, characterize and locate these precursor cells in
the human uterine lining. It also aims to obtain information on how these precursor cells function in
regenerating the uterine lining, how they interact with sex hormones and how their proliferative activity is
regulated. Information generated from this project will provide significant new insight into the functioning of
the uterine lining. It also has immediate application to common gynaecological diseases associated with
abnormal growth of the uterine lining, such as endometriosis, a disease which affects 10% of reproductive age
women causing pain and infertility. A better understanding of how these precursor cells may be involved in
endometriosis and other gynaecological diseases may ultimately lead to the development of improved medical
treatments rather than surgical intervention, which is currently the main form of treatment.
Research achievements (from final report):
The primary focus of this work was to identify adult stem cells in human and mouse endometrium, the highly
regenerative lining of the uterus that sheds and grows each month as part of the menstrual cycle. In a worldfirst we discovered rare populations of epithelial stem/progenitor cells that produce the endometrial cells that
nourish the embryo in the first 3 months of pregnancy, and mesenchymal stem-like cells that can produce fat,
bone, cartilage and smooth muscle in the culture dish. We also found a way to partially purify human
endometrial mesenchymal stem-like cells that will enable us to characterise them further and compare their
properties to mesenchymal stem cells from bone marrow and fat and use them in tissue engineering
applications. In addition we have identified that the mesenchymal stem-like cells are located around blood
vessels in human and mouse endometrium. These studies offer a new paradigm to understand the cause of
common gynaecological diseases associated with abnormal endometrial growth such as endometriosis (10% of
women affected), endometrial cancer, the commonest reproductive tract cancer, and adenomyosis.
Furthermore, it may be possible to use the mesenchymal stem-like cells in regenerative medicine for producing
new ligaments from a woman's own stem cells for improving the treatment of pelvic floor prolapse, a common
problem affecting 50% of women.
Expected future outcomes:
This project provides the first fundamental knowledge on adult stem cells in human endometrium and sets a
new paradigm in uterine biology. Future work based on this knowledge will open new avenues for increasing
our understanding on common diseases affecting the uterus, including endometriosis, endometrial hyperplasia,
endometrial cancer and adenomyosis and may lead to new and improved treatments
Name of contact:
Caroline Gargett
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
caroline.gargett@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284388
Start Year: 2004
CIA Name: Dr Isabelle Lucet
End Year: 2008
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $360,965
Title of research award:
Structural studies of the Jak and Abl kinases: a prerequisite for drug designStructural studies of the Jak and Abl
kinases: a prerequisite for drug design
Lay Description (from application):
Protein tyrosine kinases (PTK) are a large, pivotal family of signalling molecules implicated in
diseases such as cancer and immune related disorders. This fellowship aims to develop more
potent kinase inhibitors of a number of PTKs using Cytopia’s drug discovery capability coupled
with the X-ray crystallography expertise within Monash University. This innovative approach
will permit a rational structure-based drug discovery platform to be established and will lead to
the creation of a portfolio of phase I therapeutics, which will be of substantial benefit in the
medical health area.
Research achievements (from final report):
PTKs are a large, pivotal family of signaling molecules that play prominent roles in human diseases such as
cancers, cardiovascular diseases and immune related disorders, offering a fertile ground for drug discoveries.
This research award entitled "Rational Drug Design of Protein Tyrosine Kinase Inhibitors" aimed to develop
potent kinase inhibitors of a number of PTKs in collaboration with a leading Melbourne-based Biotechnology
company, Cytopia. The PTKs that we have been focusing on are the JAK kinases that play a prominent role in
cytokine signalling. Whilst members of the JAK family each present themselves as excellent drug discovery
targets for diseases of the immune system, JAK2 by dint of gene rearrangement is an important therapeutic
target for a number of haematological cancers and cardiovascular diseases. A major research achievement has
been the determination of the crystal structure of JAK2 kinase in complex with a potent and specific JAK
kinase inhibitor. This ground-breaking discovery has created new insights into the way in which JAK2
inhibitors exert their mode of action. Using Cytopia's drug discovery capability coupled with the X-ray
crystallography expertise within Monash University, we have established an internationally competitive
structure-based discovery program on JAK2 kinase inhibitors that is unparalleled in Australia. A number of
JAK2 inhibitors arising from this research have already enter formal drug development for the treatment of
haematological cancers and cardiovascular diseases and will lead to the creation of a portfolio of phase I
therapeutics, which will be of substantial benefit in the medical health area
Expected future outcomes:
The generation of drugs against JAK2 kinase could have a multimillion dollar potential. The work generated
during this award may prove to be a significant contribution to the discovery of improved JAK2 inhibitors that
could potentially have a huge impact on the health of the Australian population.
Name of contact:
Isabelle Lucet
Email/Phone no. of contact:
isabelle.lucet@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284395
Start Year: 2005
CIA Name: Dr Renea Taylor
End Year: 2008
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $271,500
Title of research award:
Role of stroma in carcinogenesisRole of stroma in carcinogenesis
Lay Description (from application):
Not Available
Research achievements (from final report):
This project utilised the technology of tissue recombination to evaluate the ablity of prostate cancer tumour
stroma to cause cancer. We were able to definitevely prove that tumour stroma plays an active role in
progression of prostate cancer in genetically 'damaged' (or defective) cells, but was unable initiate the process
of carcinogenesis in characteristically 'normal' (embryonic stem) cells. Our findings provide new information
on the relationship between tumour stroma and stem cells in the prostate that were not previously known.
Expected future outcomes:
It is expected that future drug discovery and development for novel therapeutics for prostate cancer consider
the prostatic stroma as a cellular target since those cells play an active role in the progression of carcinogenesis.
Name of contact:
Dr Renea Taylor
Email/Phone no. of contact:
Renea.Taylor@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284418
CIA Name: A/Pr Martin Lackmann
Admin Inst: Monash University
Main RFCD: Oncology and Carcinogenesis
Total funding: $204,125
Start Year: 2004
End Year: 2005
Grant Type: NHMRC Development Grants
Title of research award:
Stage II in the development of Eph/ephrin based tumor targeting reagents: Optimisation of drug efficacy and
deliveryStage II in the development of Eph/ephrin based tumor targeting reagents: Optimisation of drug
efficacy and delivery
Lay Description (from application):
In the final stage of cancer, including melanoma, tumor cells gain the ability to spread, a process called
metastasis. Altered communication between cancer and normal cells is one of the causes of this invasive
characteristic. We have started the development of novel agents that target and modulate proteins on the cell
surface that control these properties and are found in metastatic tumors. We propose to refine the targeting and
killing properties of these agents for early clinical testing.
Research achievements (from final report):
In an ongoing translational research program we evaluated the receptor tyrosine kinase (RTK) EphA3 as target
for antibody-based anti-cancer strategy. Ephs, together with their cell-bound ephrin ligands co-ordinate cell
positioning of during development. Their unscheduled presence and de-regulated activity in adults participates
in tumour metastasis and invasion. EphA3 is notably elevated in several cancers including leukaemias,
melanoma, kidney, colon, renal and prostate carcinomas. Our previous studies confirmed that the high affinity
anti-EphA3 monoclonal antibody IIIA4 effectively targets tumour cells in mouse xenografts of these cancers;
by binding to one of the ephrin-contact surfaces, pre-clustered IIIA4 triggers EphA3 signalling and
internalisation. , We now confirmed that simultaneous ephrin-A5 and IIIA4 binding dramatically accelerates
endocytosis and cellular responses: by assembling both EphA3 agonists onto the same backbone (Protein-A or
polyethylene glycol, PEG) we accelerated internalisation of the EphA3/agonist complex, and time to biological
response, 20-fold. In the context of our program, to develop EphA3-based therapeutics, this constitutes a
significant improvement of the lead reagent targeting properties, leading to production of a chimera combining
the functional features of ephrin-A5 and IIIA4. Emphasising its potential as anti-cancer therapeutic, we found
that systemic treatment of mice with PEG-conjugated IIIA4 had no adverse affects but reduced tumour growth
significantly. We demonstrated furthermore, that treatment with a IIIA4/cytotoxic reagent conjugate prolongs
the life span of leukemia-bearing mice by 100%. , In collaboration with a commercial partner we now optimise
and formulate (including humanization of IIIA4) our candidate therapeutics for progression into clinical trials.
Expected future outcomes:
Ongoing pre-clinical evaluation and optimisation of our EphA3-specific tumour targeting reagents and
characerisation of a suitable patient population for clinical trials is expected to be completed within the next 18
month. The progression of our candidate reagents into the clinic for assessment of their use for the treatment of
aggressive cancers will be a milestone achievement in our research.
Name of contact:
Martin Lackmann
Email/Phone no. of contact:
Martin.Lackmann@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 325647
Start Year: 2005
CIA Name: Dr Kara Britt
End Year: 2010
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $369,669
Title of research award:
Roles of pregnancy, estrogen and proliferation in the stem cell biology of the mammary glandRoles of
pregnancy, estrogen and proliferation in the stem cell biology of the mammary gland
Lay Description (from application):
Not Available
Research achievements (from final report):
This training fellowship allowed Kara Britt to assess the relationship between parity (childbearing), mammary
stem cells and estrogen receptor (ER) expression. This work has helped define why parous women have a
decreased breast cancer risk compared to women who have not had children. This work has lead to the
development of a mouse model of parity which enabled the effects in mammary stem cells numbers and
estrogen receptor expression to be assessed. The work led to a first author manuscript, first author review and
several co-authored publications and 2 grants for the training fellow. In addtition there are 3 mansuscripts in
preparation detailing the results of the final parts of this fellowship. Having described how ER+cells are
decreased, how mammary stem cells are isolated and affected by parity and the gene expression changes in the
breast will aid in the development of preventative breast cance therapies.
Expected future outcomes:
Three first authourship publications and a review article are in preparation. An NHMRC project grant
application is pending which used the data generated in the fellowship as preliminary data.
Name of contact:
Kara Britt
Email/Phone no. of contact:
kara.britt@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 334011
CIA Name: Prof Euan Wallace
Admin Inst: Monash University
Main RFCD: Reproduction
Total funding: $4,797,204
Start Year: 2005
End Year: 2007
Grant Type: Programs
Title of research award:
Control mechanisms of reproductive processesControl mechanisms of reproductive processes
Lay Description (from application):
This Program Grant investigates a number of important reproductive problems that affect the fertility of men,
prostate cancer and the way the mother nurtures and protects the baby during pregnancy.
The successful development of sperm requires the proper function of a number of biological processes. This
grant investigates the way in which sperm are produced, the genes that are needed to control their development,
and the way sperm propel themselves and fertilize the egg. The research also investigates how sperm are
protected during their development from infection and immunological rejection, achieved in part by a special
environment within the tubes in the testis where they grow. It appears that the general mechanisms that the
body uses to combat infections are modified within the testis and the way in which this occurs may provide
clues that could be applied to prevent the rejection of transplanted organs in general.
Some of the substances that control these processes appear to play an important role in the body’s defense
against infection.
The grant also investigates the processes that are involved in the development of prostate cancer. These
changes can occur over many years and the grant will study some substances that appear to be involved. The
work will provide new knowledge that may assist in new tests to identify whether a cancer is slow or fast
growing, thereby helping each man to decide the most sensible form of treatment.
The grant will investigate how a group of proteins, that also are involved in the control of processes discussed
above, assist the mother in protecting her baby during pregnancy. The outcomes will assist in the management
of disturbances of pregnancy that may put the fetus at risk of survival.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
Professor Euan M Wallace
Email/Phone no. of contact:
euan.wallace@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334085
Start Year: 2005
CIA Name: A/Pr Martin Lackmann
End Year: 2007
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)
Total funding: $439,500
Title of research award:
The Role of Eph/ephrin clustering and trafficking in control of tumour cell invasionThe Role of Eph/ephrin
clustering and trafficking in control of tumour cell invasion
Lay Description (from application):
Eph and ephrin proteins are important for normal development of the embryo by controlling cell positioning. In
adult tissues these proteins are present at low levels but are found at high levels in human cancers, including
skin cancers, where their presence is thought to promote aggressive tumours. We wish to understand how these
proteins control cell movement and contribute to cancer progression so that we can develop new cancer
therapies.
Research achievements (from final report):
We have unravelled an important aspect of the molecular mechanism that allowed cells to find their correct
position within tissues and is reposnible for the tendency of tumour cells to spread thoughout the body. Cell
surface proteins of the Eph receptor family navigate cells during normal and cancerous development. We have
decoded the feed-back control mechanism that controls if cells adhere to each other or are repelled. Knowledg
of this mechanism and the reposnsible molecules offers important insights into the undertsanding of cell
positioning and new targets for therapeutic intervention.
Expected future outcomes:
The controlled navigation of cells to pre-determined positions plays an essential role in the development and
maintenance of tissues. Improved understanding of the underlying principle and the rpincile proteins involved
will provide possibilities to improve treatment in many medical conditions or diseases, including cancer,
woundhealing and tissue regeneration/
Name of contact:
Martin Lackmann
Email/Phone no. of contact:
Martin.Lackmann@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334092
CIA Name: Prof Jamie Rossjohn
Admin Inst: Monash University
Main RFCD: Cellular Immunology
Total funding: $549,000
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
A structural investigation into the T-cell response to Epstein Barr Virus infectionA structural investigation into
the T-cell response to Epstein Barr Virus infection
Lay Description (from application):
X-ray crystallography is an essential tool for solving the three-dimensional structure of proteins. Proteins
control the biological processes within the cell and it is the precise shape of proteins that determines how they
function. Depending on the particular sequence of the amino acids, the so-called building unit of the proteins,
the protein molecule bends and forms a distinct, complex shape. This specific three-dimensional shape allows
the protein to undertake its specific function, such as binding to other proteins, acting as an enzyme or
interacting with nucleic acids. To determine how a protein acts, it is vital to know the precise threedimensional shape at the atomic level. This proposal is concerned with understanding the precise shape of
proteins that control the immune response to Epstein Barr Virus. Epstein Barr Virus is an ubiquitous human
pathogen that has being linked to a number of cancers. This work will further our understanding of the
immune response to Epstein Barr Virus.
Research achievements (from final report):
We gained a greater understanding of the Cytotoxic T cell Lymphocyte (CTL) immunity and antigen (Ag)
presentation, by investigating specific elements relating to the protective immune response to Epstein Barr
Virus (EBV). EBV is an important authentic, natural infection that provides an ideal model for investigating
the antiviral immune response in humans due to its ubiquity in human populations. Our underlying hypothesis
was that our studies within this system will provide an understanding of the basis for differential dominance of
particular epitopes. We progressed extremely well on the aims of this grant, having determined the crystal
structures of a number of components pertinent to this grant, which is evidenced by the publications that have
arisen from the grant.
Expected future outcomes:
The future outcomes is a greater understanding of how the immune system combats EBV infection, which may
ultimately provide a basis for the control of this infection
Name of contact:
Jamie Rossjohn
Email/Phone no. of contact:
jamie.rossjohn@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334100
Start Year: 2005
CIA Name: Prof Andrew Elefanty
End Year: 2010
Admin Inst: Monash University
Grant Type: Established Career Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $652,378
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a stem cell scientist working on the biology of human embryonic stem cells and their differentiation into
cells of mesodermal (blood, endothelium and cardiomyocyte) and endodermal (pancreatic islet cells) lineages.
Research achievements (from final report):
Research in the laboratory that I jointly head with Prof Ed Stanley is focused on the study of human pluripotent
(hESC and hiPSC) stem cells. Our core interest lies in the regulation of human pluripotent stem cell
differentiation to mesoderm and endoderm lineages, as exemplified by blood and heart and pancreatic islet
cells, respectively. , In order to facilitate this work, our laboratory has generated genetically modified human
ES cell lines into which reporter genes have been inserted by homologous recombination in gene loci that are
expressed at specific developmental stages or in specific lineages. We have targeted approximately 10 different
genes in multiple hESC lines to date. Therefore, this has enabled us to more readily identify cells developing
into blood, heart, pancreas, lung, thymus and neural cell types. Our research has been published in high quality
scientific journals and we have successfully obtained ongoung research funding ofor our laboratory., We have
also devised a reproducible differentiation protocol for human ES cells ('spin EBs'), complemented with an
animal product free, recombinant human protein containing medium (APEL) that will facilitate optimisation of
human ES cell differentiation in the presence of appropriate growth factors. This cell culture medium has been
commercialised and is now being sold by a biotechnology company, STEMCELL Technologies., Our work has
generated unique opportunities for the study of early stages of human development, the generation of
laboratory models for human diseases, the testing of pharmaceuticals and other therapeutic products and
eventually we hope to be able to produce transplantable cells for tissue repair and regeneration. The ability to
genetically modify human ES cells may translate into an ability to correct genetic abnormalities in patient
derived iPS cells in some cases.
Expected future outcomes:
A major goal of our work is to realise some of the scientific and therapeutic potential that pluripotent cells
promise. We hope to continue to develop platforms for testing of therapeutic products and the generation of
cells for replacement therapies.
Name of contact:
Andrew Elefanty
Email/Phone no. of contact:
andrew.elefanty@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 334127
Start Year: 2005
CIA Name: Dr Richard Ferrero
End Year: 2007
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Medical Microbiology not elsewhere classified
Total funding: $243,000
Title of research award:
The role of the intracellular pathogen-recognition molecule Nod1 in the host response to Helicobacter pylori
infection.The role of the intracellular pathogen-recognition molecule Nod1 in the host response to Helicobacter
pylori infection.
Lay Description (from application):
The report in 1982 by two Australian clinicians, Drs Marshall and Warren, of a link between a spiral-shaped
bacterium, Helicobacter pylori, and stomach disease in humans was to prove one of the ground breaking
discoveries of medical research in the last 20-30 years. Despite extensive studies since, including the
sequencing of the entire genomes of two different H. pylori isolates, many issues relating to H. pylori disease
remain unanswered. For instance, it is still not known why all infected individuals develop inflammation of the
stomach lining, yet only a proportion (15-20%) will go on to develop severe diseases, such as peptic ulcer
disease and stomach cancer. Recent work from our groups has identified the mechanism by which H. pylori
induces host responses in the cells lining the stomach, the epithelial cell. The interaction of the bacterium with
these cells represents its first contact with the host, and sets the scene for the development of immune
responses in the stomach. From their position on the outside surfaces of epithelial cells, certain strains of H.
pylori are able to deliver a bacterial component into host cells, thus triggering an inflammatory response in the
latter. Curiously, a host molecule called Nod1, which is present on the inside of cells and not on the surface,
acts as an internal sensor by interpreting the entry of this H. pylori component as a danger signal for the host.
The aim of the project will be to characterise the resulting defence mechanisms that are induced by Nod1 in
order to prevent the colonisation of the stomach by H. pylori bacteria. It is expected that this work will address
questions concerning the role of host immune defence mechanisms in H. pylori infection and stomach disease.
Amongst the possible public health benefits of this work will be the development of novel therapies to reduce
inflammation in the stomach by blocking Nod1 responses to H. pylori bacterial components.
Research achievements (from final report):
Stomach cancer and peptic ulcer disease (PUD) impose huge burdens on the health and wealth of populations
worldwide. A key initiator in the development of these diseases is the bacterium, Helicobacter pylori, which
colonises the cells that line the stomach wall, thereby inducing inflammation. These inflammatory responses
form part of the host's defence system against infection, but also create the conditions necessary for the
development of cancer and PUD. The main objective of the research project was to understand the role of a
host protein, Nod1, in these responses. We were thus able to demonstrate Nod1 regulation of genes that code
for members of a family of proteins with bacteria-killing properties. In particular, we showed that H. pylori
strains that specifically induce host cell responses via Nod1, and which are more frequently associated with
severe disease, induce Nod1-dependent up-regulation of the bacterial-killing protein, hBD-2. We were also
able to demonstrate for the first time the direct killing of H. pylori by substances produced by host cells and,
moreover, performed studies to identify other genes regulated by Nod1. A potential outcome of the latter work
will be the identification of host markers that may be used to predict progression towards severe diseases, such
as stomach cancer and PUD. Finally, we identified an entirely new mechanism whereby H. pylori and other
disease-causing bacteria can induce Nod1 activation, and hence inflammation, in host cells. This finding should
open new areas of investigation for the prevention of such diseases.
Expected future outcomes:
A better understanding of how H. pylori induces inflammation; the identification of host markers that may be
used to predict progression towards severe H. pylori disease; the identification of a novel secretion mechanism
by which bacteria release pro-inflammatory factors and that may be "co-opted" to develop novel vaccine
strategies.
NHMRC Research Achievements - SUMMARY
Name of contact:
Richard L. Ferrero
Email/Phone no. of contact:
Richard.Ferrero@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334196
CIA Name: Dr Kate Fulton
Admin Inst: Monash University
Main RFCD: Medical Biochemistry: Other
Total funding: $219,188
Start Year: 2005
End Year: 2008
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Development of Bioinformatic tools for Protein Folding StudiesDevelopment of Bioinformatic tools for Protein
Folding Studies
Lay Description (from application):
Not Available
Research achievements (from final report):
An online database of protein folding was developed and thoroughly tested. The database contains important
information relating to the folding behaviour of more than 50 proteins. Understanding protein folding is key to
understanding their role in physiology, medicine and disease. The database is the first of its kind and represents
a key step forward in making this important data available to researchers worldwide. In addition this is the first
time the data has been stored in a standardised way, which will provide benefits across the field. The database
is available at http://pfd.med.monash.edu.au
Expected future outcomes:
We anticipate that the database will have several benefits in the field of protein folding. First, it is a key
resource for researchers in the field, allowing all the important folding data for a protein to be retrieved easily
and quickly. Second, it will promote standards for experimentation and data publication. It will also encourage
bioinformatic analyses to be performed.
Name of contact:
Ashley Buckle
Email/Phone no. of contact:
Ashley.Buckle@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334202
CIA Name: Prof Gail Risbridger
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $144,950
Start Year: 2005
End Year: 2006
Grant Type: NHMRC Development Grants
Title of research award:
Development of a serum based test for aggressive prostate cancer.Development of a serum based test for
aggressive prostate cancer.
Lay Description (from application):
Prostate cancer is relatively slow growing, taking decades to reach clinical significance. A critical phase in the
progression of prostate cancer is the transformation from latent (or dormant) to aggressive tumours; hence the
saying that many men die with prostate cancer, rather than of prostate cancer. We aim to develop a test utilising
inhibin-activin proteins as surrogate markers of aggressive disease based on our previous studies of a
significant correlation between the expression of inhibins in tissues from men with high grade prostate cancer.
This study aims to validate the correlation using serum rather than a tissue based assay.
Research achievements (from final report):
There is an urgent need to develop new tests for prostate cancer because of the inabilyt of the current PSa test
to distinguish between benign and malignant disease and to predict relapse following surgery. The aim of this
study was to test the utility of inhibin proteins as a prognostic marker of recurrent disease. AS prostate cancer
becomes more aggressive it looses it abilty to respond to hormones and the tumor continues to grow in the
absence of androgens; this is considered as end stage aggressive cancer and is untreatable. Using cell lines that
change from being androgen dependent to independent we were able to demonstrate conclusively that inhibin
was a crucial regulator of this switch in hormone independence, that it is an upstream regulator of VEGF, a
factor well known to be involved in metastatic disease. However, using specimens the outcomes of the study
failed to show proof of the concept that inhibin measurements could predict patient outcome and therefore the
utility of further development of inhibin as a diagnostic marker in this regard.
Expected future outcomes:
The basic biology describing the role of inhibin in the tranformation of prostate cancer cells from being able to
grow in the absnce of homrones is in preparation for publication, the development of inhibin as a surrogate
marker for this process in patient specimens remains unproven.
Name of contact:
Gail Risbridger
Email/Phone no. of contact:
gail.risbridger@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334370
Start Year: 2005
CIA Name: Dr Huseyin Sumer
End Year: 2009
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $272,813
Title of research award:
Chromatin modification of reprogrammed cellsChromatin modification of reprogrammed cells
Lay Description (from application):
Not Available
Research achievements (from final report):
One of the most exciting advances in cell biology has been the ability to wind back the developmental clock of
adult cells back to an embryonic state. In this project I investigated the different methods of reprogramming
differentiated cells to an embryonic state including somatic cell nuclear transfer, cell fusion to embryonic stem
cells and inducing pluripotency by defined factors. I analysed various aspects of the cells before and after
reprogramming and was able to add new insight into the reprogramming process.
Expected future outcomes:
By characterising the resultant reprogrammed cells we will further improve our understanding of the
mechanisms involved, and elucidate processes involved in reprogramming and developmental biology.
Name of contact:
Hailee Gyngell
Email/Phone no. of contact:
hailee.gyngell@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 345438
Start Year: 2005
CIA Name: Dr Ana Traven
End Year: 2009
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $293,250
Title of research award:
Mechanisms of SQ/TQ cluster domain function in DNA damage responseMechanisms of SQ/TQ cluster
domain function in DNA damage response
Lay Description (from application):
Not Available
Research achievements (from final report):
The focus of my research project were factors in the model organism yeast, which have dual roles in the cell.
The first function of these factors is regulating processes required for growth and division of cells. These
pathways are highly conserved between the yeast model and human cells and are relevant to diseases such as
cancer. I have identified that a protein complex called Ccr4-Pop2-NOT functions in an essential process during
cell division-assembly of septin proteins at the cell periphery. This process is well conserved in human cells
and is important for human diseases (e. g. cancer, neurodegenerative diseases). Septin proteins are also
important for infectious diseases, in particular life-threatening infections with fungal pathogens (e.g. Candida
albicans). This part of my research provided links to the second function of these factors: formation of a
specialized structure called the cell wall, which is relevant for virulence of human fungal pathogens. Fungal
pathogens, such as Candida albicans, are infecting humans more prevalently and mortality is huge (30-50%). I
identified that Ccr4-Pop2-NOT, as well as an SQ/TQ cluster domain protein called Mdt1 are required for cell
wall construction in fungi. These results have implications for designing more efficient antifungal therapies.
Expected future outcomes:
I identified new factors required for construction of yeast cell walls-a process essential for virulence of fungal
pathogens and antifungal drug resistance. We will use this new knowledge to further delineate pathways
essential for fungal pathogenesis and for screens aimed at antifungal drug development.
Name of contact:
Ana Traven
Email/Phone no. of contact:
ana.traven@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 350302
Start Year: 2005
CIA Name: A/Pr Timothy Cole
End Year: 2007
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Immunology not elsewhere classified
Total funding: $417,500
Title of research award:
A T Cell-Specific GR promoter Determines Responsiveness to Glucocorticoids in Different Immune
CompartmentsA T Cell-Specific GR promoter Determines Responsiveness to Glucocorticoids in Different
Immune Compartments
Lay Description (from application):
Synthetic glucocorticoids, such as dexamethasone and prednisolone, are commonly used as potent antiinflammatory steroid drug during the treatment of major human trauma and cancer. A side-effect of these very
high steroid doses is a major down-regulation of the immune system, particularly massive death of important
immune cells called T-cells, which can have a major impact on patient recovery and potential mortality.
These T cells are particularly sensitive to glucocorticoid-induced cell death and have very high levels of
receptors for these steroids called glucocorticoid receptors (GRs). We have discovered a unique GR gene
promoter (designated 1A) that is active in T cells. Very little is known about how this gene promoter is
regulated. This promoter may be a useful therapeutic target to block T cell death (caused by steroids) during
recovery from injury, infection and cancer. Separation of anti-inflammatory and side-effects such as high Tcell death or blockade of these effects on T cells would have a major impact on patient immune status and
recovery, and reduce the incidence of debilitating side-effects. Therapeutic down-regulation of this T cellspecific GR gene promoter could lead to targeted blockade of steroid-induced T cell death and help maintain a
strong immune system. This application brings together a unique team of investigators (CIs) that have a
strong history of collaboration in this area with recent publications in very high ranking international journals.
The CIs bring a multi-disciplined approach combining endocrinology, molecular biology and cellular
immunology to determine the underlying mechanisms of steroid actions and their effects on immune function.
Both Dr Cole (CIA) and Dr Godfrey (CIB) have excellent track records in this area.
Research achievements (from final report):
This proposal investigated the expression, regulation and physiological significance of the glucocorticoid
receptor (GR) gene 1A promoter. We performed an extensive analysis of GR1A expression in steady state
mouse T and B lymphocytes using RTPCR on different developmental stages. This confirmed that higher GR
expression is driven by the GR1A promoter in T cells, and to a lesser extent in B cells, and that GR1A driven
GR expression is also regulated by glucocorticoids and by TCR ligation. We have floxed the GR1A promoter
within the mouse genome using gene-targeting in mouse ES cells and these have been used to generate
chimeric mice. Chimeras are currently being assessed for germ-line transmission. In agreement with our
equivalent analysis in mice, we have shown that in the human thymus, GR1A3 appears to drive higher levels of
GR which peak during TCRbeta selection at the pre-T cell stage, indicating a conserved and potentially key
role for GR1A driven GR expression at this stage of T cell development. Unexpectedly, among peripheral
human lymphocyte populations, B cells were the most sensitive to death, suggesting glucocorticoid-induced
cell death of peripheral B cells may be a mechanism by which GCs exert their therapeutic effects in the clinic.
Expected future outcomes:
Therapeutic targeting of this T cell-specific GR promoter may prevent glucocorticoid-induced T cell death and
help maintain a stronger immune system in the face of clinical glucocorticoid therapy.
Name of contact:
Timothy J Cole
Email/Phone no. of contact:
tim.cole@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 359272
CIA Name: Dr BIRCAN ERBAS
Admin Inst: Monash University
Main RFCD: Applied Statistics
Total funding: $274,300
Start Year: 2005
End Year: 2008
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Novel applications of statistical methods to breast cancer dataNovel applications of statistical methods to breast
cancer data
Lay Description (from application):
Not Available
Research achievements (from final report):
During my fellowship I established the first DCIS and mammographic density study funded by the National
Breast Cancer Foundation. Related to this, my colleagues and I were awarded a NHMRC funded behavioural
research project to examine women's experience of DCIS diagnosis and awareness and attitudes of surgeons to
clinical practice recommendations of DCIS treatment. In addition, I initiated a collaborative research project on
estimating future disease burden of leading cancers and chronic diseases. Our method (Erbas, Hyndman and
Gertig, 2007) was adopted Australian Institute of Health and Welfare for forecasting cancer in Australia. In
2007, I was awarded the prestigious International Union Against Cancer -ICRETT Fellowship to visit Harvard
University, Boston, USA (fully funded) for 30 days to develop research collaborations in developing statistical
models for predicting breast cancer mortality and incidence with Professor Marvin Zelen and colleagues. , , As
a result of the valuable training provided by the fellowship I am developing an independent research program
on DCIS and mammographic density. My national and international reputation in this field is growing.
Internationally, I am collaborating with a group of researchers in Cambridge on DCIS and mammographic
density. I have also further expanded my research on environmental health - a topic related to my PhD studies
funded through an NHMRC PhD scholarship. I am a CIA on an NHMRC funded project on asthma admissions
and pollen and a chief investigator on another NHMRC project on Victorian Bushfire's.
Expected future outcomes:
At present my combined skills in epidemiology and biostatistics provides and relevant training has given me
the opportunity to develop and establish epidemiological studies on DCIS and environmental epidemiology
which are highly relevant both nationally and internationally.
Name of contact:
Bircan Erbas
Email/Phone no. of contact:
b.erbas@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384104
Start Year: 2006
CIA Name: Prof Gail Risbridger
End Year: 2010
Admin Inst: Monash University
Grant Type: NHMRC Research Fellowships
Main RFCD: Clinical Sciences not elsewhere classified
Total funding: $664,574
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
My research focus is Urology and Prostate Cancer, but my previous contributions to Andrology and
Endocrinology of the Testis provide a significant breadth of expertise and a sustained record of contribution to
Men's Reproductive Health. As part of my strategy to establish a comprehensive prostate cancer research
program, I expanded my studies on the biology of stromal-epithelial cell interactions in normal and tumour
tissue using tissue recombination with animal and human specimens. More recently I pioneered the use of stem
cells for recombination studies combining stem cell biology with endocrinology. Recognition of my
contribution to Andrology & Urology by Industry, led to establishment of a collaborative research network
with Schering AG and the integration of research teams from Industry and Academia. As the scientific research
program developed and I recruited the expertise of Urology and Pathology colleagues, it was necessary to
establish infrastructure to underpin the national research effort in Australian Prostate Cancer Research,
including a National tissue bank and informatics support. Finally I developed a productive collaboration with
the Australasian Cochrane Centre to address key questions in public health relating specifically to prostate
cancer. My continued role in Men's Health builds upon my training in male reproductive endocrinology and
continues with advisory roles in Andrology Australia and the Freemasons Foundation Centre for Men's Health.
Expected future outcomes:
Under my direction, the overall goal of my program is to progress our understanding of the basic biology of the
prostate gland, in order to develop new therapies for prostate cancer (PCa), BPH or prostatitis. All of these
diseases are a significant burden on health care systems worldwide and I anticipate my research outcomes will
enable clinical trials of new therapies.
Name of contact:
Gail.Risbridger
Email/Phone no. of contact:
gail.risbridger@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 384107
Start Year: 2006
CIA Name: Prof David Jans
End Year: 2008
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $491,768
Title of research award:
Role of the microtubule network in nuclear transport: potential use in gene deliveryRole of the microtubule
network in nuclear transport: potential use in gene delivery
Lay Description (from application):
Transport of key proteins that regulate growth and other processes, into and out of the nucleus, the site of gene
transcription, is central to the function of eukaryotic cells. Knowledge of the process is largely based on
studies using semi-intact cell systems, however, meaning that the role of cytoskeletal elements in nuclear
transport has been largely overlooked. Intriguingly, in vivo studies, including our own relating to signalling
molecules important in the regulation of cancer, clearly implicate the cellular microtubule (MT) network as
playing an integral role in nuclear import. We propose to carry out a detailed examination of the mechanistic
basis of the dependence of nuclear import on the MT network of 3 molecules regulating cancer. We will
compare the properties of these molecules to those of other nuclear localizing molecules, as well as examine
the ability to mediate nuclear import of similar MT-associating sequences from viral and other proteins. The
results will establish for the first time, the generality of the dependence of nuclear protein import on
cytoskeletal elements. Since the movement of large DNA molecules by simple diffusion is a limiting factor in
non-viral gene delivery approaches, the possibility of applying this knowledge to facilitate the transport of
DNA encoding therapeutic gene products to the nucleus of target cells, will also be assessed for the first time.
We will use the modular sequences that confer interaction with the MT network to assist gene transfer by
including them in modular constructs we have designed with this in mind. We will thus be able to test directly
for the first time whether MT-interaction can enhance the delivery of DNA to the nucleus and reporter gene
expression, with obvious application in gene therapy approaches.
Research achievements (from final report):
Regulated delivery of protein to the cell nucleus is vital to physiological and pathological processes such as
development, cancer and viral infection, as well as a major consideration for therapeutic development for
cancer and gene therapies. We have shown that microtubules, a network of cellular filaments, plays key roles in
regulating the nuclear trafficking of viral and cancer-related proteins by appearing to act as tracks to move
proteins toward the nucleus. We have characterised in detail the mechanisms involved, including how proteins
leave the MT tracks and move into the nucleus. This identifies novel targets for therapeutics for use in cancer
and virus infection. We have also exploited these mechanisms to enhance the delivery of cargoes to the cell
nucleus, with the potential to develop new vehicles for the delivery of therapeutics (e.g. anti-cancer drugs and
genetic material) to the nucleus.
Expected future outcomes:
Our novel observations of MT-dependent nuclear trafficking should produce enhanced gene therapy
approaches that use the MT network to efficiently deliver DNA to cell nuclei, as well as new approaches to
treat cancer/viral infection via inhibition of MT-dependent nuclear delivery of specific cancer-related/viral
proteins.
Name of contact:
David Jans
Email/Phone no. of contact:
david.jans@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384113
Start Year: 2006
CIA Name: A/Pr Martin Lackmann
End Year: 2010
Admin Inst: Monash University
Grant Type: Established Career Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $548,878
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
The NH&MRC Fellowship provided opportunities to explore my basic research interest in cellular and
molecular mechanisms underlying invasive growth of tumour tissue and to use findings from this research to
develop a new anti-cancer therapeutic for the treatment of leukaemias and of solid tumours. Based on my initial
discovery that a cell guidance and signalling protein, called EphA3, is found almost exclusively on tumour
cells and on tumour supporting tissue cells, I established a R&D program to explore this EphA3 protein as
therapeutic target for the treatment of cancer patients. Under my direction, a team of collaborating scientists
assessed the anti-cancer potential of an anti-EphA3 antibody in animal cancer models and developed assays to
detect EphA3 in human tumour samples, allowing selection of cancer patients that may be treated with tis
antibody. A clinical-grade antibody, generated under licence by KaloBios Pharmaceuticals was FDA approved
for clinical testing and a clinical trial in leukaemia patients opened in a US cancer centre in 2010, the final year
of my Fellowship., In parallel, basic research in my lab revealed therapeutic potential of a further protein on
cancer cells, ADAM10, and its intimate involvement in the function of EphA3 and related cell surface proteins.
Our findings allowed development of monoclonal antibodies that specifically block the function of this
ADAM10 protein and are assessed as second-generation anti-cancer therapeutics. The key findings from the
basic research in my laboratory were published in top scientific journals and their clinical potential was
protected in several patent applications.
Expected future outcomes:
The clinical trial of our therapeutic antibody now includes Melbourne, Adelaide and Brisbane hospitals, so that
Australian cancer patients may benefit from this treatment in the immediate future. Pending on the success in
leukemias, the antibody will also be trialled in solid tumour patients.
Name of contact:
Martin Lackmann
Email/Phone no. of contact:
Martin.Lackmann@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 384137
Start Year: 2006
CIA Name: Prof Christina Mitchell
End Year: 2008
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $505,523
Title of research award:
Characterization of the phosphoinositide 5-phosphatase SKIP.Characterization of the phosphoinositide 5phosphatase SKIP.
Lay Description (from application):
Growth factors and insulin stimulate a complex array of signals inside the cell, which are important for both
cell survival and metabolism. A central intracellular signaling enzyme that initiates lipid messages that promote
glucose uptake into the cell and promote cell survival is that generated by the PI3-kinase. This enzyme has
increased activity in many cancers, and is also important in diabetes when the enzyme may be suppressed. Our
grant proposes to investigate the function of another enzyme called SKIP which acts within the cell to oppose
the functions of the PI3-kinase. Several lines of evidence indicate SKIP may be important in both development
and cancer. SKIP has been identified as a putative candidate gene for a developmental disorder known as
Miller Dieker syndrome. This disease is associated with facial and significant brain abnormalities. In addition
the SKIP gene is located on a chromosome that is frequently deleted in breast and colon cancer. SKIP is an
enzyme that functions to remove phosphate molecules from PI3-kinase signaling molecules. SKIP has been
shown to prevent glucose uptake into the cell by breaking down PI3-kinase signals. We have recently
demonstrated SKIP phosphatase activity can be inhibited by binding to another protein called suppressor of
death domains (SODD). We plan to investigate the effects this complex has on SKIP enzyme activity, and how
this complex plays a role in regulating PI3-kinase signals that promote glucose uptake. Secondly, we plan to
investigate the function of SKIP in an intact animal by making mice which lack SKIP(knock out mice). Given
SKIP is implicated in a developmental syndrome and insulin signaling, we can delineate the functional
significance of SKIP and the molecular pathways regulated by this enzyme.
Research achievements (from final report):
This study has characterised a novel signal terminating enzyme called SKIP, that regulates the actin
cytoskeleton and thereby cell migration and in addition regulates insulin stimulated glucose uptake. The
inositol polyphosphate 5-phosphatase SKIP, opposes an important intracellular pathway generated by the PI3kinase. SKIP exhibits increased activity in certain cancers and may promote cancer cell migration and invasion.
SKIP is also implicated in a number of other human diseases including developmental defects of the human
cerebral cortex, perhaps as a result of abnormal cell migration. This grant has characterised the role SKIP plays
in regulating the actin cytoskeleton revealing it may function to regulate the migration and invasion of both
normal cells and tumours. In addition the grant has demonstrated that SKIP is essential for normal embryonic
development and mice which lack SKIP die mid gestation. These studies have identified a novel gene that is
important in human development.
Expected future outcomes:
We predict SKIP may play an important role in regulating the normal migration of brain cortex cells during
embryonic development and in future studies will develop mouse models with targeted and inducible deletion
of SKIP in specific tissues during embryonic development
Name of contact:
Prof Christina Mitchell
Email/Phone no. of contact:
christina.mitchell@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384147
Start Year: 2006
CIA Name: A/Pr Tony Tiganis
End Year: 2008
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Immunology not elsewhere classified
Total funding: $454,023
Title of research award:
Regulation of TNF and SFK signalling in immune cells by TCPTPRegulation of TNF and SFK signalling in
immune cells by TCPTP
Lay Description (from application):
Tumour necrosis factor (TNF) is a potent proinflammatory cytokine that plays an important role in immunity
and inflammation. TNF acts on the cell surface to activate two key cellular communication or signalling
pathways: the mitogen-activated protein kinase (MAPK) pathway and the nuclear factor kappaB (NFkappaB)
pathway. The relative activation of the two pathways can dictate whether cells live and proliferate or
differentiate or otherwise die in response to TNF, and therefore determine the nature of the immune or
inflammatory response. The T-cell protein tyrosine phosphatase (TCPTP) is known to be important in the
immune system and serves as a negative regulator of inflammation. Our preliminary studies have identified
TCPTP as a selective regulator of TNF-induced MAPK but not NFkappaB signaling. TCPTP exerts its effects
by inactivating Src family kinases (SFK) which are themselves integral to immune and inflammatory
responses. In this proposal we will elucidate the molecular basis for TCPTP function in TNF- signalling and
characterise the role of TCPTP in TNF and SFK functions in immune cells, in particular T-cells.
Research achievements (from final report):
T cells play a central role in the immune response acting as both direct effectors and as regulatory cells to
control the magnitude and duration of an immune response to invading pathogens and tumour cells. The
primary event leading to T cell activation is the triggering of the T cell receptor (TCR). Our results have
identified TCPTP as a novel regulator of T cell development and function acting on the TCR. Our results
provide new insights into processes that are fundamentally important in the control of T cell mediated
immunity.
Expected future outcomes:
Identify TCPTP as an important regulator of T cell-mediated immunity
Name of contact:
Tony Tiganis
Email/Phone no. of contact:
Tony.Tiganis@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384149
Start Year: 2006
CIA Name: Prof Tony Tiganis
End Year: 2010
Admin Inst: Monash University
Grant Type: Established Career Fellowships
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $548,878
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
One of our key findings in the last five years has been in delineating the potential beneficial effects of reactive
oxygen species in insulin sensitivity and consequentially, the potentially detrimental effects of antioxidants in
the development of type 2 diabetes.
Expected future outcomes:
Delineating the precise nature by which reactive oxygen species can be both good and bad.
Name of contact:
N/A
Email/Phone no. of contact:
Tony.Tiganis@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 384189
Start Year: 2006
CIA Name: A/Pr Jun-Ping Liu
End Year: 2008
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $438,521
Title of research award:
Signalling to telomeres: mechanisms of action of TGFbSignalling to telomeres: mechanisms of action of TGFb
Lay Description (from application):
Cell lifespan is controlled by the enzyme called telomerase. High telomerase activity makes cell immortal as
seen in cancer. We recently show that high telomerase activity can be inhibited by transforming growth factor b
(TGFb). This may partly explain why TGFb inhibits cancer and induces cell ageing. This project furthers our
investigation into the mechanism(s) by which TGFb inhibits telomerase. We recently noted for the first time
that TGFb binds to telomerase gene directly, and this is controlled by another protein called c-myc. This work
will determine how telomerase is controlled by a balance between TGFb and c-myc in order to find ways to
control telomerase and therefore cancer. We will use a combination of sophisticated techniques of cell
molecular biology and biochemistry to pinpoint and target different molecules implicated in the actions of
TGFb. This study will serve as an important baseline for more applied research in controlling ageing and
cancer from development.
Research achievements (from final report):
This study establishes a novel concept that tumor cell immortalization can be controlled by the cytokine TGFbeta family members. This is a significant development for strategic planning to arrest cancer cell development
using these cytokines. Proof of principle has been achieved by injecting the TGF-beta family member BMP7
into xenograft tumors in mice. The results show that tumor growth is completely inhibited by BMP7 with a
treatment scheme of one injection in another day for two weeks. Analysis of the tumor sections demonstrates
that tumor cells undergo ageing and death following administering of BMP7, consistent with inhibition of
telomerase activity and induction of telomere shortening. Further mechanism investigations show that TGFbeta members employ Smad3 protein that migrates into the nucleus. Smad3 binds to the telomerase hTERT
gene promoter DNA and interacts with the oncogene c-myc, resulting in repression of the hTERT gene, thereby
telomerase inhibition and telomere shortening. BMP7 is a potent cytokine that triggers ~30% shortening of
telomeres in cultured cancer cells and tumor sections. Thus, BMP7, as well as perhaps other TGF-beta family
members, and their intracellular intermediate proteins such as Smad3, represent novel agents discovered for
therapeutic candidates of many types of cancers including breast cancer and cervical cancers that have been
demonstrated in this project.
Expected future outcomes:
This project has led to a new avenue of mechanisms in cytokine regulation of tumor development.
Understanding of the new mechanisms from cytokines to tumor cell development will provide significant
insight into therapeutic strategies against tumor development..
Name of contact:
Jun-Ping Liu
Email/Phone no. of contact:
jun-ping.liu@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384194
Start Year: 2006
CIA Name: Dr Jian Li
End Year: 2008
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Pharmaceutical Sciences and Pharmacy
Total funding: $349,823
Title of research award:
Novel therapeutic strategy against multidrug-resistant gram-negative bacteriaNovel therapeutic strategy against
multidrug-resistant gram-negative bacteria
Lay Description (from application):
In the past two decades, there has been a marked decline in discovery and development of new antibiotics
while there has been a remarkable increase in resistance to the currently available antibiotics. The growth in the
number of resistant bacteria and lack of antibiotics available for treatment is very significant with gramnegative bacteria, such as Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas
maltophilia. Colistin, an old antibiotic that has been used little over the last 40-50 years, has been 'taken off the
shelf' and is now being used as a last line of defence to treat people with infections caused by these bacteria.
Clearly, doctors and their infected patients will be in an even more precarious position than currently exists if
resistance to colistin increases. We have discovered a novel therapeutic strategy that is able to reverse colistin
resistance in P. aeruginosa. The studies proposed in this project will investigate this novel strategy across a
range of multidrug-resistant bacteria and provide the information essential for rational use in patients. We
propose that such a novel therapeutic strategy will provide a powerful weapon for the war on these 'superbugs'.
Research achievements (from final report):
In the past two decades, there has been a remarkable increase in resistance to currently available antibiotics, in
particular in Gram-negative bacteria Pseudomonas aeruginosa, Acinetobacter baumannii and
Stenotrophomonas maltophilia. Unfortunately it is unexpected that new antibiotics will be available for these
'superbugs' (Infectious Diseases Society of America) in the next decade. , In this project, we systematically
examined a novel therapeutic strategy, combination of polymyxins and macrolides. This combination is able to
not only synergistically kill P. aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia, but
also attenuate bacterial pathogenesis of P. aeruginosa by inhibiting production of major virulence factors at
certain concentrations. This combination holds a great promise for a new therapeutic option for treatment of
infections caused by these 'superbugs'., We first reported that colistin-resistant A. baumannii isolates are much
more susceptible to the antibiotics, including macrolides, to which their susceptible parent isolates are usually
resistant. This novel finding, together with other important achievements in our colistin pharmacology
research, has led to a successful NIH R01 grant which is administered through Monash University. This fouryear NIH project (US$2,213,562) will investigate rational antibiotic combinations against Gram-negative
'superbugs' using a systematic pharmacological approach. , This study provides the information essential for
rational use of colistin combinations in patients with cystic fibrosis or critically-ill patients with Gram-negative
respiratory tract infections.
Expected future outcomes:
This project provides important pharmacological knowledge for clinical use of the combinations of colistin and
macrolides to treat infections caused by Gram-negative pathogens which are resistant to current antibiotics. A
project grant will be submitted to NIH, North American Cystic Fibrosis Foundation or NHMRC to further
examine their efficacy in patients.
Name of contact:
Jian Li
Email/Phone no. of contact:
Jian.Li@pharm.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384195
CIA Name: Prof Peter Rogers
Admin Inst: Monash University
Main RFCD: Obstetrics and Gynaecology
Total funding: $488,273
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of endometrial angiogenesis and lymphangiogenesisRegulation of endometrial angiogenesis and
lymphangiogenesis
Lay Description (from application):
Unlike almost all other parts of the adult body, the blood vessels of the endometrium (lining of the uterus) grow
and breakdown each month as part of the menstrual cycle. The endometrium also has a very unusual
distribution of lymph vessels, which are responsible for removing excess fluid from the tissues and also have
an important role in the immune system. The overall aim of this research is to understand how growth and
regression of these vascular systems are controlled in the endometrium. The information will have immediate
relevance to a number of clinical problems in which abnormal changes in the blood and lymph vascular
systems are observed (e.g. tumour growth, wound healing). This includes a number of significant problems
relevant to women's health. Non-menstrual bleeding (often termed breakthrough bleeding) is one of the most
common gynaecological problems suffered by women, and can be particularly worrying as it may be a
symptom of more serious diseases such as uterine cancer. Breakthrough bleeding can occur under a wide range
of hormonal conditions and is thought to be due, at least in part, to faulty uterine blood vessel growth.
Endometrial cancer is another serious disease and is the most frequently diagnosed malignancy of the female
reproductive system. When diagnosed early, this cancer responds well to therapy. However, treatment of this
disease is much more difficult when an increase in blood vessel growth is observed and the tumours interact
with the lymphatic vascular system. An aim of this research is to investigate changes in uterine blood and
lymph vessel growth associated with breakthrough bleeding and endometrial cancer.
Research achievements (from final report):
Unlike most other parts of the adult body, the blood and lymph vessels of the endometrium (lining of the
uterus) grow and breakdown each month as part of the menstrual cycle. In this research, we provided new
information about the mechanisms responsible not only for the growth of blood vessels in the endometrium,
but also their maturation. We also provided novel data about lymph vessels in the endometrium, the factors that
are responsible for their growth and development, and the changes in these vessels associated with the use of
progestin-only contraceptives and in endometrial cancer. These results are relevant to our understanding of
normal function in the endometrium, but also to the understanding of various gynaecological diseases disorders
with a vascular component, particularly breakthrough bleeding, which is a common side effect experienced by
women using progestin-only type contraceptive therapies.
Expected future outcomes:
These results have led to the development of novel hypotheses regarding the mechanism responsible for the
abnormal blood and lymph vessels that are observed in women who use progestin-only contraceptives and who
experience breakthrough bleeding.
Name of contact:
Prof Peter Rogers
Email/Phone no. of contact:
Peter.Rogers@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384201
CIA Name: Prof Malcolm Sim
Admin Inst: Monash University
Main RFCD: Epidemiology
Total funding: $222,888
Start Year: 2006
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Occupational exposure to lead compounds and human cancerOccupational exposure to lead compounds and
human cancer
Lay Description (from application):
This study aims to investigate whether there is a link between cancer (in particular cancer of the stomach, lung,
kidney and central nervous system) and occupational exposure to lead compounds. There are only a few
published cohort studies available on occupational exposures in use and applications of lead compounds,
despite the widespread use of these compounds in the past 50 years. Since the late 1980s the use of lead
compounds in Australia has decreased, but Australian and world lead production has increased. Australia is
the world's biggest producer of lead. The precise number of lead workers worldwide is unknown but there are
likely to be more than 2 million workers of which many are in developing countries where control of lead
exposure is unsatisfactory and occupational exposure limits are considerably higher than in developed
countries. Evidence for or against cancer risk with exposure to lead compounds , in particular inorganic lead,
will therefore have implications for many Australian and international workers. This is also important for
health risk assessment for environmental contamination in the Australian community. In our study we will
review the state government archived records of about 8,000 lead workers in New South Wales, Victoria and
South Australia, who took part in lead compound exposure surveys and had blood tests in the 1970s, 1980s and
1990s, as part of government lead regulations in force at the time. We will then match the details of these
workers against the National Cancer and Death registry data to calculate cancer rates. This should involve a
sufficient number of workers to enable us to undertake a comprehensive health evaluation of cancer risk and
exposure to lead compounds.
Research achievements (from final report):
This project has assembled a significant historical cohort of former workers in lead exposed industries and
jobs. By linking the records of these workers to the national Australian registries of death and cancer we have
been able to assess the mortality and cancer experience of these workers.
Expected future outcomes:
Through update linkages to the cancer and death registires, this cohort can continue to provide information
about cancer incidence and cause of death in this group as it's members age.
Name of contact:
Malcolm Sim
Email/Phone no. of contact:
Malcolm.Sim@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384219
Start Year: 2006
CIA Name: Dr Brendan Jenkins
End Year: 2008
Admin Inst: Monash University
Grant Type: Career Development Fellowships
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $272,000
Title of research award:
The opposing roles of STAT1 & STAT3 signalling elicited byIL-6 family cytokines in cancer &
inflammation.The opposing roles of STAT1 & STAT3 signalling elicited byIL-6 family cytokines in cancer &
inflammation.
Lay Description (from application):
Not Available
Research achievements (from final report):
Studying an altered form of a molecule called gp130 which is in every cell of the body, our aim is to learn
more about how and why inflammation disorders and cancers develop. We have discovered a specific mutation
in gp130 that leads to over-activation of gp130 and results in the formation of stomach inflammation (gastritis)
and cancer in mice. Furthermore, we have discovered that over-activation of gp130 also causes an increased
inflammatory response with relevance to human diseases such as septic shock and peritonitis. As an example of
the significance of these findings to human health, stomach cancer is the second most common cause of cancerrelated deaths worldwide, and the molecular mechanisms by which chronic stomach inflammation and cancer
develop in some people are unknown. , One of the key achievements of our work has been identifying that
over-activation of gp130 causes over-activation of another protein inside cells called STAT3. STAT3 is
actually over-activated in up to 50% of human stomach cancers, and our results identify for the first time how
STAT3 can become over-activated and therefore result in chronic inflammation and the subsequent
uncontrolled growth of epithelial cells that line the stomach wall., We also note that considering the common
molecular and cellular events that contribute to the inflammatory program, importantly our research findings
will extend to further define the mechanisms by which uncontrolled inflammation can contribute to other
cancers including liver, colon and prostate which are also characterized by STAT3 over-activation.
Expected future outcomes:
Understanding how STAT3 elicits specific biological responses, and the cell/tissue-specific context in which
this occurs, will ultimately identify novel biomarkers to screen/detect disease at an early stage, as well as
provide the molecular basis on which to design next-generation therapeutic strategies and reagents to prevent
inflammation and cancer.
Name of contact:
Brendan Jenkins
Email/Phone no. of contact:
brendan.jenkins@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384232
Start Year: 2006
CIA Name: Dr Richard Ferrero
End Year: 2008
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Medical Microbiology not elsewhere classified
Total funding: $336,143
Title of research award:
Identification of novel colonisation factors in Helicobacter pyloriIdentification of novel colonisation factors in
Helicobacter pylori
Lay Description (from application):
The discovery by Drs Marshall and Warren of the bacterium Helicobacter pylori, and its role in stomach
disease, has proven to be one of the major break-throughs of the late 20th century. Indeed, several common
ailments of the upper digestive tract that were once thought to be untreatable, or which could only be treated by
radical surgery, are now managed through the use of antibiotics and acid-blocking substances. The efficacy of
these treatments has, however, been affected by the increasing rates of H. pylori resistance to these antibiotics
in the general community. Furthermore, the limited choice of antibiotics available for use in anti-H. pylori
treatment regimens, and the side-effects associated with several of these compounds, suggest that there is a
need to develop new therapies against this bacterial infection. This, however, will necessitate a greater
understanding of the mechanisms by which H. pylori is able to colonise and survive in the mucus layer
covering the stomach. To address this point, we have used a gene profiling technique to compare gene
expression in H. pylori bacteria displaying high and low levels of colonisation in a mouse model. For this,
mouse-colonising H. pylori bacteria were attenuated through extensive passaging on culture media in the
laboratory. Five genes were identified as being poorly expressed in the attenuated bacteria. These genes are
proposed to encode putative H. pylori colonisation factors. The aim of the project is to characterise these
factors, and to determine the roles of two of these, which are involved in the production of vitamin B6, in the
colonisation of the stomach. This work will contribute to a greater understanding of the factors involved in H.
pylori colonisation of the stomach. Amongst the possible public health benefits of this work is the
identification of molecular targets for the development of new therapies for the prevention and treatment of H.
pylori infection.
Research achievements (from final report):
Advances in the field of Helicobacter pylori pathogenesis have provided only rudimentary knowledge about
how the bacterium colonises the stomach. To address this question, we used the mouse-colonising H. pylori
SS1 strain and laboratory-attenuated variants to study the genes involved in gastric colonisation. Two of the
identified genes, pdxA and pdxJ, were shown to be involved in synthesis of vitamin B6, an important molecule
for numerous cellular metabolic reactions. While the biological function of vitamin B6 and its biosynthesis
pathways have been extensively examined in the non-pathogenic bacterium, E. coli, little is currently known
regarding the synthesis of this vitamin in human pathogens. We have demonstrated that vitamin B6
biosynthesis is required for optimal growth of H. pylori. Using several techniques, including electron
microscopy and live cell imaging, we have shown that besides its recognised metabolic functions, vitamin B6
is required for motility in H. pylori. Disruption of the pdxA gene resulted in bacteria that were non-motile in
culture media as they did not have functional flagella, or "tails". Importantly, we demonstrated that H. pylori
PdxA was essential for chronic colonisation in mice. This work identifies vitamin B6 biosynthesis enzymes as
novel virulence factors for bacterial pathogens. Interestingly, a number of human pathogens possess pdxJ/A
genes, and, in some of these bacteria (e. g. Salmonella enterica and Vibrio cholerae), vitamin B6-dependent
enzymes have been reported to be involved in the synthesis of various structures required for colonisation. The
absence of similar genes in mammals suggests that Pdx enzymes may represent ideal candidates as new
therapeutic targets.
Expected future outcomes:
Previous human H. pylori vaccines have been ineffective at inducing strong H. pylori specific immune
responses in humans. The findings of our study, identifying vitamin B6 biosynthesis as a requirement for
NHMRC Research Achievements - SUMMARY
optimal growth and bacterial colonisation, are expected to assist in the future development of a live attenuated
vaccine which may be effective against H. pylori infection.
Name of contact:
Dr Richard Ferrero
Email/Phone no. of contact:
Richard.Ferrero@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384241
CIA Name: A/Pr Martin Lackmann
Admin Inst: Monash University
Main RFCD: Oncology and Carcinogenesis
Total funding: $647,232
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
EphA3-modulated cell positioning in tumour invasion and neovascularisation.EphA3-modulated cell
positioning in tumour invasion and neovascularisation.
Lay Description (from application):
During the progression of human cancers, tumor cells increasingly lose their ability to communicate and coexist in a regulated fashion with normal cells to maintain the status quo. Because they multiply uncontrollably,
tumour cells spread into surrounding tissue and can invade other organs of the body. The Ephs and interacting
ephrins are proteins on the cell surface, and their communication controls the position of cells within the body
tissues and organs, but also in tumours. Together with collaborators at the Ludwig Institute for Cancer
Research and the Queensland Institute for Medical Research we produced two proteins, an antibody and a
recombinant ephrin that bind one of the Eph proteins on tumour cells. The antibody allowed us to locate Eph
in tumours, where it appears surprisingly not only on tumour cells but also on tumour blood vessels. When
attached to a redioactive compund it selectively targets the cancer cells and in an animal study prolonged the
survival of mice with leukemia significantly. We will now investigate the exact role of this Eph protein in
tumour blood vessels. We will then study what happens in tumours when a toxic antibody-drug compound
targets this tumour and starts to kill tumour cells. Finally, we will devise a novel reagent that combines the
properties of the antibody with the properties of the ephrin into a single protein, which can deliver a cell-killing
drug exclusively and most efficiently to tumour cells containing the Eph protein on its surface.
Research achievements (from final report):
The EphA3 cell surface receptor is an enzyme, which directs the migration of cells during organ development,
a function contributing significantly to growth and spreading of tumours. EphA3 is considered as prominent
cancer gene in leukemia, melanoma, colon, lung, breast and prostate cancer. We discovered previously that
within tumours EphA3 is found mostly prominently on blood vessels and connective tissue. , During the course
of this grant we developed an antibody against EphA3 for the treatment of cancer. In collaboration with a
biopharmaceutical company we produced therapeutic versions of the antibody, now termed KB004, and tested
their anti-tumour activity in a range of experimental (animal) tumour models as a basis for upcoming clinical
trials in cancer patients. In experimental models of prostate, lung and colon tumours KB004 antibody
effectively binds to the new tumour blood vessels and by destroying vessel integrity reduces blood flow and
leads to regression of tumours. The findings from our studies have prompted the design of clinical trials in a
range of cancer patients to commence in 2010. The use of the anti-EphA3 antibody as anti-cancer therapeutic
and diagnostic was patented in the course of this grant, and scientific publications are being submitted.,
Continuation of therapeutic antibody development is now funded by an NH&MRC program grant (colon
cancer), by Cancer Australia/ Prostate Cancer Foundation (prostate cancer), while studies with collaborators in
Canada and Germany, to unravel cell-cell communication during blood vessel formation are funded the Human
Frontiers Science Organisation.
Expected future outcomes:
The promise of the anti-EphA3 antibody as potent anti-cancer thearpeutic in a broad range of solid tumours and
in many leukemias has triggered a significant interest to evaluating its potential to treat a large range of cancer
patients in clinical trials in Australian hospitals.
Name of contact:
Martin Lackmann
Email/Phone no. of contact:
Martin.Lackmann@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384242
Start Year: 2006
CIA Name: A/Pr Martin Lackmann
End Year: 2008
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $457,268
Title of research award:
Functional analysis of the molecular switch that regulates ADAM10-mediated cleavage of RTK ligands in
tumour cells.Functional analysis of the molecular switch that regulates ADAM10-mediated cleavage of RTK
ligands in tumour cells.
Lay Description (from application):
We have determined the structure and identified the region of the ADAM10 metalloprotease that controls its
specific cleavage of ephrins. Ephrins and their receptors (Ephs) direct cell positioning during development by
controlling cell-cell adhesion and repulsion. In adult tissues these proteins are present at low levels but are
found at high levels in human cancers, including skin cancers, where they are thought to promote aggressive
tumours. The switch to cell repulsion occurs by cleavage of the ephrin by ADAM10 which also functions in
other cancer promoting events by cleaving growth factors. Our structure reveals how Eph-bound ephrin is
specifically targeted by ADAM. We will now determine the relevance of this mechanism for other ADAM10
targets, and design drugs to bind this region and inhibit ADAM function, which we will test in assays
measuring tumour cell movement and growth, with the aim of developing therapies to block cancer
progression.
Research achievements (from final report):
ADAM metalloproteases are enzymes on the surface of most cells which control the communication between
cells by releasing surface-bound messenger proteins and other growth factors. It is widely accepted that this
cell surface protein shedding by ADAM proteases is regulated from within cells. For example, signalling by
growth factor receptors or mechanisms underlying detachment of adherent cells are known to involve the
ADAM proteases. However, the mechanism linking growth factor receptor signalling and ADAM shedding
activities have remained elusive. , In our studies we have demonstrated that ephrin ligands, cell surface proteins
that interact with Eph receptors on neighbouring cells to control cell-cell adhesion, are cleaved by the
ADAM10 protease only once they have bound and activated Eph receptors. We discovered that this Eph
receptor activation is accompanied by a significant change in conformation: it triggers extension of the
intracellular part of the receptor away from the cell membrane and only this extended conformation permits the
tight association with the ADAM protease that is necessary for effective cleavage of the ephrin bound to the
receptor from an interacting cell. This finding defines a new regulatory concept in cell communication, where
feed-back control is provided by a switch in the conformation of the receptor cytoplasmic domain rather than
by cytosolic signalling pathways. The important roles of the implicated proteins in normal and pathological cell
function make this concept of profound importance for biological and translational research.
Expected future outcomes:
The insights from our research guided the development of monoclonal antibodies recognising specific parts of
ADAM proteins and affecting ADAM activity. Considering the central role of ADAM proteases in rheumatoid
arthritis, heart disease and cancer, these anti-ADAM antibodies will be developed for therapeutic applications.
Name of contact:
Martin Lackmann
Email/Phone no. of contact:
Martin.Lackmann@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384261
CIA Name: Prof Paul Hertzog
Admin Inst: Monash University
Main RFCD: Reproduction
Total funding: $507,271
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Function of a novel interferon in reproductiona and developmentFunction of a novel interferon in
reproductiona and development
Lay Description (from application):
It is important to understand the factors responsible for maintaining fertility, pregnancy and to prevent infection
of the developing fetus and the uterus. The latter is an important general problem in women. We have
identified a new protein that our current evidence suggests is involved in reproduction, embryonic or fetal
development. This new protein is related tot he interferon family of proteins that are best characterised by their
important functions in protecting the host from viral infections and cancer. We propose to undetake a detailed
study to determine when and where the new interferon is produced in the reproductive tract and during
pregnancy and its importance in the maintenance of pregnancy and in protection against fetal/uterine infection.
Research achievements (from final report):
This project achieved the first steps in the characterisation of a new protein that we discovered. This protein is
related to the interferon family of proteins that are not normally expressed, but induced during infection then
help to protect the body from disease by a series of specific antiviral and antibacterial actions as well as by
stimulating the immune system. However the new protein, designated interferon epsilon, is normally expressed
exclusively in the reproductive tract, is not induced by infection. We characterised the intricate molecular and
genetic elements that control the expression of this new protein; these findings will contribute important
information to understand its function. Our studies generated the world's first animal model of mice deficient in
the gene that encoded interferon epsilon. These mice were healthy and fertile which means that the new
interferon is not essential for reproduction, development or fertility. We expect this protein might be impotrant
in the control of reproductive tract infections.
Expected future outcomes:
The future direction of this work will be to study the role of interferon epsilon in reproductive tract infections.
We will also produce this protein to determine its special properties and whether it is of any potential clinical
benefit. IN addition we will generate antibodies and assays to determine its
Name of contact:
Paul Hertzog
Email/Phone no. of contact:
paul.hertzog@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384268
Start Year: 2006
CIA Name: Dr Brendan Jenkins
End Year: 2008
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $472,771
Title of research award:
The Opposing Roles of STAT1 and STAT3 Signalling by IL-6 Family Cytokines in Inflammation and
TumourigenesisThe Opposing Roles of STAT1 and STAT3 Signalling by IL-6 Family Cytokines in
Inflammation and Tumourigenesis
Lay Description (from application):
Stomach cancer is the second most common cause of cancer-related deaths worldwide, and results in the yearly
death of several thousand people in Australia alone. We have discovered a specific mutation in a gene for a
receptor molecule called gp130 that results in the formation of stomach cancer in mice. Strikingly, mice with
this mutation are also highly susceptible to clinically-relevant experimental models of septic shock and
peritonitis, two chronic inflammatory disorders induced by bacterial infection. We are now aiming to
understand the exact molecular events by which this mutation results in the uncontrolled growth of epithelial
cells that line the stomach wall, as well as uncontrolled regulation of the immune system leading to local and
systemic inflammation. At the molecular level, the mutation in gp130 leads to over-activation of two
signalling molecules, Stat1 and Stat3, which are also used by a range of other receptors to transmit specific
cellular responses. In the context of cancer and inflammation, Stat1 and Stat3 have opposing roles (ie Stat3
promotes cancer and can be both anti/pro-inflammatory, while Stat1 suppresses cancer and is proinflammatory), although as yet, the contribution of the gp130 receptor in directing Stat1 and Stat3 activation in
these disorders is not known. Our proposal employs established strategies and unique mouse models to
specifically address how the mutation in gp130 can orchestrate the opposing biological functions of these two
molecules to drive stomach cancer and inflammation. The identification of mechanisms by which gp130dependent activation of these two molecules causally relate to inflammation and stomach cancer will ultimately
provide novel and rational approaches to target these molecules for the screening and treatment of various
inflammatory disorders and cancers, including those of the stomach.
Research achievements (from final report):
Studying an altered form of a molecule called gp130 which is in every cell of the body, our aim is to learn
more about how and why inflammation disorders and cancers develop. We have discovered a specific mutation
in gp130 that leads to over-activation of gp130 and results in the formation of stomach inflammation (gastritis)
and cancer in mice. Furthermore, we have discovered that over-activation of gp130 also causes an increased
inflammatory response with relevance to human diseases such as septic shock and peritonitis. As an example of
the significance of these findings to human health, stomach cancer is the second most common cause of cancerrelated deaths worldwide, and the molecular mechanisms by which chronic stomach inflammation and cancer
develop in some people are unknown. , One of the key achievements of our work has been identifying that
over-activation of gp130 causes over-activation of another protein inside cells called STAT3. STAT3 is
actually over-activated in up to 50% of human stomach cancers, and our results identify for the first time how
STAT3 can become over-activated and therefore result in chronic inflammation and the subsequent
uncontrolled growth of epithelial cells that line the stomach wall., We also note that considering the common
molecular and cellular events that contribute to the inflammatory program, importantly our research findings
will extend to further define the mechanisms by which uncontrolled inflammation can contribute to other
cancers including liver, colon and prostate which are also characterized by STAT3 over-activation.
Expected future outcomes:
Understanding how STAT3 elicits specific biological responses, and the cell/tissue-specific context in which
this occurs, will ultimately identify novel biomarkers to screen/detect disease at an early stage, as well as
provide the molecular basis on which to design next-generation therapeutic strategies and reagents to prevent
inflammation and cancer.
NHMRC Research Achievements - SUMMARY
Name of contact:
Brendan Jenkins
Email/Phone no. of contact:
brendan.jenkins@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384285
Start Year: 2006
CIA Name: Dr Peter Janes
End Year: 2010
Admin Inst: Monash University
Grant Type: Career Development Fellowships
Main RFCD: Medical and Health Sciences not elsewhere classified
Total funding: $462,290
Title of research award:
The role of Eph-ephrin clustering and trafficking in control of tumour cell invasion.The role of Eph-ephrin
clustering and trafficking in control of tumour cell invasion.
Lay Description (from application):
Not Available
Research achievements (from final report):
I have investigated the role of a family of cell surface receptors called Eph receptors, which are over abundant
in many cancers in which they regulate tumour vascularisation, invasion and metastasis. These receptors and
their ephrin binding partners control cell-cell interactions, switching between attachment and segregation. My
research has elucidated mechanisms determining this switch, which relies on the ADAM10 protease, and its
regulation by Eph receptor activity. Also I have shown that distinct Eph receptor subclasses can co-operate by
co-clustering, such that receptors can be cross-activated even when their binding partners are absent. These are
highly significant findings, resulting in high impact publications (Cell, PLoS Biology, PNAS) with potential
benefits for cancer treatment. Towards this end we have raised antibodies against the substrate binding pocket
of ADAM10, to block cleavage of ephrin and prohibit cell-cell detachment. Given that ADAM10 and the
related ADAM17 also shed a number of other cell surface proteins important in disease (including EGFR/erbB
ligands and receptors, TNF alpha), such inhibitors are actively sought and would have wide therapeutic
potential.
Expected future outcomes:
We will continue to develop and evaluate ADAM10 targeted therapeutic antibodies for clinical application.
The cross-talk between Eph receptors has implications for anti-Eph targeted therapeutics, and will also be
evaluated in tumour models using an EphA3 therapeutic antibody developed in our laboratory, currently in
phase I clinical trials.
Name of contact:
Peter Janes
Email/Phone no. of contact:
peter.janes@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 384347
CIA Name: Dr Michelle Dunstone
Admin Inst: Monash University
Main RFCD: Analytical Biochemistry
Total funding: $259,252
Start Year: 2006
End Year: 2010
Grant Type: Early Career Fellowships (Australia)
Title of research award:
A structural investigation of human serum proteinsA structural investigation of human serum proteins
Lay Description (from application):
Not Available
Research achievements (from final report):
The studies are important for the understanding of how Legionella pneumophila persists in the environment
and how it causes the disease, Legionnaires' disease. This research has also help me develop skills used to
explore important proteins in other pathogenic micro-organisms including Photorhabdus luminescens,
Enteropathogenic E. coli and Pasteurella multocida., Furthermore I have completed a number of studies
looking at how the immune system recognises and targets pathogens. Taken together, I have developed a set of
skills that have led to the structural and functional investigation of pathogenic factors and the immune response
to disease. Potential benefits include the development of therapeutic drugs, novel antibiotics and vaccines.
Expected future outcomes:
My work on Plu-MACPF proteins led to research on the whole MACPF family of pore forming toxins, from
structural to functional studies. This is anticipated to show how pore forming toxins can be used for either drug
development or adapted for drug delivery.
Name of contact:
Michelle Dunstone
Email/Phone no. of contact:
michelle.dunstone@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 384349
CIA Name: Dr Natalie Borg
Admin Inst: Monash University
Main RFCD: Tumour Immunology
Total funding: $188,063
Start Year: 2006
End Year: 2008
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Structural and functional analysis of natural killer T-cell recognition of lipid CD1dStructural and functional
analysis of natural killer T-cell recognition of lipid CD1d
Lay Description (from application):
Not Available
Research achievements (from final report):
Fat-based fragments are normally found within our body, but sometimes our body is exposed to 'unfamiliar'
fragments, like in the event of a bacterial infection. The purpose of the CD1d molecule in our body is to
capture these fat-based fragments and present them to our immune system for surveillance by patrol cells called
Natural Killer T (NKT) cells. NKT cells determine whether the presented fragments are 'familiar' or
'unfamiliar' to our body by interacting with them. In the event that an NKT cell finds an 'unfamiliar' fragment it
sends a 'message' to our immune system, alerting it to put up it's defences and mount an attack. For this reason,
this event is crucial to our defence against bacterial infection, but also has significant wider implications.
Diseases such as atherosclerosis, autoimmune disease and allergy are associated with an imbalance in the
'message' that NKT cells send. In addition NKT cells can enhance our immune response to some cancers and
have a role in fighting tumours. Given the importance of the NKT cell 'message' in a broad range of human
diseases, they can be used therapeutically to send a more favourable 'message' for a particular disease. My main
research achievments during the course of my Peter Doherty training fellowship involved using X-ray
crystallography to determine the structure or the shape of an NKT cell receptor on it's own and also in complex
with the CD1d molecule presenting a fat-based fragment. This has provided the first visual insight into how our
immune system recognises fat-based fragments and is a key step to manipulating the 'message' in the future.,
Expected future outcomes:
My future research will involve trying to dissect exactly how different fat-based fragments are recognised by
our immune system, and what is it about the different structures that translates into a different 'message'. These
studies will continue to use X-ray crystallography as a tool to determine the structures of the relevant
molecules.
Name of contact:
Natalie Borg
Email/Phone no. of contact:
natalie.borg@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384354
CIA Name: Dr Helen Kelsall
Admin Inst: Monash University
Main RFCD: Epidemiology
Total funding: $306,750
Start Year: 2006
End Year: 2009
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Cancer incidence, effect of diet & physical activity on breast cancer prognosis, disability & qual of life in
ageing...Cancer incidence, effect of diet & physical activity on breast cancer prognosis, disability & qual of life
in ageing...
Lay Description (from application):
Not Available
Research achievements (from final report):
This Public Health Postdoctoral Fellowship has provided me with experience in cancer epidemiology, record
linkage, and cancer registries, as well as the opportunity as a chief or coinvestigator to undertake public health
research on projects in several important fields. Analysis of data from the Melbourne Collaborative Cohort
Study has provided a greater understanding of the relationship between socioeconomic status and survival from
cancer. A study is in progress investigating the relationship between risk and prognostic factors for breast
cancer of different immunohistochemical subtypes. A study using qualitative and quantitative methodologies is
investigating Australian's views about privacy and participation in research. The Australian arm of an
international study is investigating musculoskeletal disorders in nurses as a key occupational health workforce
group. Key health outcomes such as multisymptom illness and psychological health have been further studied
in Australian Gulf War veterans, and a study is being develeoped to follow up their longer term health and
wellbeing almost 20 years after the 1990-91 Gulf War and ten years after our group first studied their health.
Expected future outcomes:
Evidence for factors that affect survival from cancer will continue to emerge, and record linkage has the
potential to develop in a way that could facilitate research in this field. Veteran health research with follow up
of Gulf War veterans 20 years after the Gulf War will provide valuable insights into the longer term effects of
deployment and of health and wellbeing in this veteran group.
Name of contact:
Dr Helen Kelsall
Email/Phone no. of contact:
helen.kelsall@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 384359
Start Year: 2006
CIA Name: Dr Marguerite Buzza
End Year: 2010
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Medical Biochemistry: Proteins and Peptides
Total funding: $195,384
Title of research award:
Studies on the role of Testisin in fertility and cancer using knockout mice.Studies on the role of Testisin in
fertility and cancer using knockout mice.
Lay Description (from application):
Not Available
Research achievements (from final report):
This research focused on a recently discovered family of proteases (enzymes) found on the surface of cells
throughout the body. These proteases are known to have roles in normal tissue development, but when
dysregulated or over-expressed, they are thought to be involved in disease progression and cancer. In this
study, the function of the membrane anchored protease - Matriptase was investigated. Matriptase is known to
be highly expressed in, and causally-linked to the growth and spread of many epithelial tumors, however the
mechanism by which it causes tumor progression remains largely uncharacterised. The function of Matriptase
in normal cells was examined in an effort to gain information on its functions in tumor cells. The role of
Matriptase in the epithelium lining the gastrointestinal tract was investigated in cell culture studies and using
matriptase-deficient mice. These studies revealed that matriptase plays a critical role in forming the intestinal
epithelial barrier. Defects in this barrier are known to be involved in the pathogenesis of inflammatory bowel
diseases (IBD) and IBD associated colon cancers. Matriptase was found to regulate the expression of proteins
important for forming the tightness of the junctions between the epithelial cells lining the intestine. Analysis of
diseased human tissues showed that Matriptase is markedly decreased in patients with Crohn's disease and
ulcerative colitis. Taken together, our data suggest that decreased Matriptase expression may be involved in the
pathogenesis of inflammatory bowel diseases.
Expected future outcomes:
These findings provide an opportunity for the development new drugs that mimic the action of matriptase for
the treatment of inflammatory bowel diseases. In addition, as cell-cell adhesion is an important regulator of
tumor cell proliferation and metastasis, these findings also provide a new direction for identifying the function
of matriptase in cancer.
Name of contact:
Marguerite Buzza
Email/Phone no. of contact:
mbuzza@som.umaryland.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 395525
Start Year: 2006
CIA Name: Dr John Price
End Year: 2010
Admin Inst: Monash University
Grant Type: Career Development Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $462,290
Title of research award:
Identification and characterization of novel molecular modulations of tumour cell metastasisIdentification and
characterization of novel molecular modulations of tumour cell metastasis
Lay Description (from application):
Not Available
Research achievements (from final report):
The spread of a cancer to distant organs, known as metastasis, is the major cause of death and morbidity in
cancer patients. To enhance health outcomes in cancer patients, the identification of mediators of metastasis are
needed so that new treatments for this aspect of cancer can be identified. Our research primarily focusses upon
breast cancer metastasis and has been successful in identifying several stress-related genes that impact upon
metastasis through their ability to modulate cancer cell growth, survival, migration, and invasion. Moreover,
examination of breast cancer patient specimens demonstrated that these genes associated with increased
recurrance and reduced overall patient survival, demonstrating the importance of these genes in breast cancer
progression. This work has revealed the importance of stress-related pathways in breast cancer metastasis and
provides a number of novel genes that could be used in breast cancer prognosis and targeted by new drugs to
impact upon breast cancer metastasis. To address the latter, we have been successful in establishing a novel cell
based screening model which we will use in future research to isolate novel drugs for the treatment of breast
cancer metastasis. As well as studying the impact of these genes upon metastasis we have also identified that a
number of these genes play a role in cancer cell resistance to particular therapies. Therefore, this research
provides valuable information in relation to the biology of breast cancer metastasis, therapeutic resistance,
novel prognostic markers and potential novel therapeutic targets.
Expected future outcomes:
The identification of novel therapeutic compounds that target the action of these stress-related proteins and
their development as novel agents in combating breast cancer metastasis.
Name of contact:
John T. Price
Email/Phone no. of contact:
john.price@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 400251
CIA Name: Dr Helen Abud
Admin Inst: Monash University
Main RFCD: Oncology and Carcinogenesis
Total funding: $606,268
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
APC mutation and the initiation of colorectal cancerAPC mutation and the initiation of colorectal cancer
Lay Description (from application):
Colorectal (or bowel) cancer is a major health problem in Australia. At present it is the most common cancer,
approximately 1 in 21 Australians will develop the disease in his/her lifetime. The risk of bowel cancer
increases with age, with the risk rising progressively and sharply from the age of 50. Current therapies for
advanced colorectal cancer are not very effective. Mortality from colorectal cancer is high, being second only
to lung cancer as the leading cause of cancer death in Australia. The development of colorectal cancer is
affected by both genetic and environmental factors. Colorectal cancer progresses through a number of distinct
pathological stages. This is thought to be the result of the progressive aquisition of mutations in genes that
normally ensure a balance between cell growth and cell death. Mutations in a gene known as APC are
associated with the very early stages of tumour formation in at least 80% of colorectal tumours. Our research
is aimed at understanding how alterations in APC influence the behaviour and growth of colonic cells. We
have developed a novel system where normal mouse colon can be maintained and grown for up to 2 weeks in a
Petri dish. Alterations in the APC gene and other colon cancer genes will be introduced into the normal
epithelial cell lining and the effects on the growth and behaviour of the cells in organ culture will be analysed.
Our hypothesis is that changes in the APC gene affects the way cells migrate, divide and move. This work
should improve our knowledge of the cellular changes that occur during tumour initiation in the bowel and
aims to contribute to the design of new therapies for early intervention in colon cancer.
Research achievements (from final report):
We have developed a new system for studying how cancers of the digestive tract are intiated by using organ
culture of mouse tissues. This culture system allows us to study the very first changes in tissue structure during
the development of cancers and to design therapies that will target these early events.
Expected future outcomes:
We have already identified new genes that play roles in intestinal cancer and expect in the near future to be
able to use live cell imaging to investigate cancer initiation in real time.
Name of contact:
Dr Helen Abud
Email/Phone no. of contact:
helen.abud@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 406620
Start Year: 2006
CIA Name: Dr Adam Hart
End Year: 2008
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $491,768
Title of research award:
The regulation of pluripotency and self-renewal in embryonic and germline stem cells.The regulation of
pluripotency and self-renewal in embryonic and germline stem cells.
Lay Description (from application):
Regulation of self-renewal and developmental potential in embryonic and germline stem cells. The capacity of
some stem cells to self-renew and under specific conditions, give rise to all adult cell types, a property known
as pluripotency , is the key to unlocking the potential of cell based therapies. The development of stem cell
based therapies promises to revolutionize the treatment of many common human diseases. For instance, in
neurodegenerative conditions such as Parkinsons disease, normal embryonic stem cells grown in culture could
be used to replace the lost or disabled neurons in the patient. Many other conditions including diabetes, cystic
fibrosis, myocardial infarction (heart attack) and stroke could potentially be treated with stem cell based
therapies. Understanding the molecular regulators that govern establishment and maintenance in culture of
stem cell lines derived from embryos and from germ cells is the primary goal of this study. We will use wellestablished techniques to genetically manipulate mouse embryonic stem cells and embryos to examine the role
of a specific gene, NANOG. Named after the Celtic legend of Tir NaNog (land of the ever young). When
NANOG was forced to remain active, embryonic stem cells were able to grow in media deficient in factors
usually required for self-renewal and did not lose their pluripotency even when treated with chemical agents
that usually induce differentiation. Understanding the full capacity of NANOG to influence stem cell selfrenewal and elucidation of the underlying molecular pathways regulated by this gene will provide valuable
insights into the establishment and manipulation of stem cell lines from embryonic and adult tissues.
Research achievements (from final report):
The pluripotency homeobox gene NANOG was identified as an early genetic marker of human germ cell
tumors. This marker can be now be used to reliably diagnose the earliest forms of testicular and metastatic
germ cell tumor, enabling more rapid identification and treatment of this life threatening disease (Hart, AH., et.
al., 2005)., We investigated the role of the NANOG gene in normal development and cancer using genetically
manipulated cell lines and mice, demonstrating that this gene is essential for stem cell survival in the early
embryo. The genetically manipulated stem cells and mouse lines haveyielded an important insight into the
molecular basis of stem cell survival and self renewal. These tools will now enable further research into the
molecular regulation of embryonic and adult stem cells and the pathogenesis of germ cell tumours and some
other forms of cancer. , Identification and manipulation of nanog and other key stem cell genes will provide a
theoretical basis for the manipulation of embryonic and adult stem cell lines prior to application in cell based
therapies in a range of acute and chronic degenerative diseases., The genetically manipulated mice represent a
valuable resource for further investigation of the putative cancer stem cell that is thought to be the originating
cell of many tumor types, including mammary, colorectal, germ cell. leaukemias and lung cancer.
Expected future outcomes:
1. The germ cell tumor marker Nanog will be used in the clinical identification and classification of testicular
and metastatic tumours of germ cell origin. The Nanog mutant mice will be used to identify and analyse adult
stem cells.
Name of contact:
Adam Hart Phd
NHMRC Research Achievements - SUMMARY
Adam Hart
Email/Phone no. of contact:
adam.hart@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 410505
Start Year: 2007
CIA Name: Dr Neal Williams
End Year: 2009
Admin Inst: Monash University
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Biotechnology not elsewhere classified
Total funding: $373,250
Title of research award:
Structure determination of Fms and Kit kinases and their inhibtors for directed drug designStructure
determination of Fms and Kit kinases and their inhibtors for directed drug design
Lay Description (from application):
Tyrosine kinases are a large and important family of enzymes that play a fundamental role in the control and
communication between cells. When damaged or uncontrolled, these enzymes can contribute to the
development of diseases such as cancer and immune related disorders. This proposal aims to develop
therapeutics targeted at the tyrosine kinases using a combination of the Structure Biology expertise at Monash
University and the drug discovery platform technologies of Cytopia Pty Ltd. Promising drug candidates already
identified by Cytopia will be analysed at their site of action using X-ray crystallography. This information will
enable a rational process of modification and improvement of the candidate drugs. The development of a range
of therapeutics for Phase I clinical trials will be of enormous benefit to Australia’s medical industry and pubic
health.
Research achievements (from final report):
Protein Tyrosine Kinases are a large, pivotal family of signaling molecules that play prominent roles in human
diseases such as cancers, cardiovascular diseases and immune related disorders, offering a fertile ground for
drug discoveries. This research award entitled "Rational drug design using protein kinase structures" aimed to
develop potent kinase inhibitors of a number of PTKs in collaboration with a leading Melbourne-based
Biotechnology company, Cytopia. We have been focusing on the JAK kinases that play a prominent role in
cytokine signalling. While members of the JAK family each present themselves as excellent drug discovery
targets for diseases of the immune system, JAK2 is an important therapeutic target for a number of
haematological cancers and cardiovascular diseases. The JAK2 structure has been determined by us previously,
but the closely related JAK1 structure was unknown and desirable for designing drugs with sufficient
specificity. A major research achievement has been the determination of the crystal structure of JAK1 kinase in
complex with potent and specific JAK kinase inhibitors. This has enabled new insights into the way JAK2
inhibitors exert their mode of action. A number of JAK2 inhibitors arising from this research have already enter
formal drug development for the treatment of haematological cancers and cardiovascular diseases and will lead
to the creation of a portfolio of phase II therapeutics, which will be of substantial benefit in the medical health
area.
Expected future outcomes:
The generation of drugs against JAK2 kinase could have a multimillion dollar potential. The work generated
during this award may prove to be a significant contribution to the discovery of improved JAK2 inhibitors that
could potentially have a huge impact on the health of the Australian population.
Name of contact:
Prof. Jamie Rossjohn
Email/Phone no. of contact:
jamie.rossjohn@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 418033
Start Year: 2007
CIA Name: Dr Richard Burke
End Year: 2013
Admin Inst: Monash University
Grant Type: NHMRC Enabling Grants
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $1,008,896
Title of research award:
Australian Drosophila Biomedical Research Support FacilityAustralian Drosophila Biomedical Research
Support Facility
Lay Description (from application):
Breakthroughs in biomedical research frequently come from the study of model organisms, one of the most
important of which is the vinegar fly, Drosophila melanogaster. In Australia, Drosophila is used in biomedical
research with a particular focus on understanding processes that result in human cancer or are associated with
birth defects or inherited diseases. Drosophila-based research is funded by bodies such as the Anti-Cancer
Foundation, the National Health and Medical Research Council (NH and MRC) and the National Institutes of
Health of the USA. This proposal seeks to establish infrastructure support for Drosophila research in the form
of a central collection of key research stocks, a centralized facility for the importation of genetically defined
stocks and a facility for the generation of transgenic Drosophila for use in biomedical research.
Research achievements (from final report):
The Australian Drosophila Biomedical Research Support Facility (ADBRSF) was established to assist and
promote research in Australia using the vinegar fly Drosophila melanogaster, a powerful animal model system
for investigating many aspects of medical biology, with numerous cost, speed and technical advantages over
vertebrate models. The main role of the ADBRSF has been as a hub for the importation and distribution of
Drosophila stocks into Australia from international stock centres and collaborating laboratories. Centralizing
this process has meant that only one quarantine facility is required in Australia, achieving significant savings in
personnel and building maintenance. , In the seven years of this grant, over 20 thousand fly strains have been
imported into the country for 31 independent research groups at 14 separate institutions including Universities,
government research bodies such as the CSIRO and medical research institutes including the Peter MacCallum
Cancer Centre, Queensland Brain Institute and the Garvan Institute of Medical Research. Australia's biosafety
has been greatly enhanced by having well-trained personnel dedicated to safe quarantine practises. The
ADBRSF has also curated a collection of Drosophila stocks, facilitating the sharing and exchange of resources
between Australian researchers., The researchers supported by the ADBRSF have made significant advances
using Drosophila to study cancer, cell cycle control, metastasis, stem cell biology, DNA repair mechanisms,
programmed cell death, neural function, neurodegenerative diseases, growth defects, chromosomal
abnormalities and disease vector control. 194 publications have been enabled through the use of this facility,
with 56 postdoctoral fellows and 95 PhD students benefitting from our services.
Expected future outcomes:
The ADBRSF has now established itself as viable, self-sufficient, pay-for-use facility that will continue to
serve Australian researchers for years to come. As the availability of Drosophila strains increases dramatically
with the advent of novel technologies, the demand for these strains will also rise, ensuring a vital future role for
the facility.
Name of contact:
Richard Burke
Email/Phone no. of contact:
richard.burke@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 433615
CIA Name: A/Pr Terrance Johns
Admin Inst: Monash University
Main RFCD: Oncology and Carcinogenesis
Total funding: $526,683
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Signalling networks as targets for antibody therapy in glioma.Signalling networks as targets for antibody
therapy in glioma.
Lay Description (from application):
Antibodies are a major component of the bodies immune system that bind (i.e. stick) to foreign substances such
as viruses. Once bound, these antibodies can activate other parts of the immune system, which help destroy the
foreign substance. Analogous to the situation above, a number of institutions are testing antibodies that bind to
cancer cells, in order to determine if they are able to destroy these cells. It is also possible to generate
antibodies that bind to receptors on the surface of cancer cells and block their function. If you target a receptor
critical to the growth or survival of a cancer cell in this way, then swtiching-off this signal may inhibit tumor
growth. In this proposal we plan to test a panel antibodies that recognize receptors important to the growth of
brain cancer. Two of these antibodies have been generated and the other two will be made as part of this
proposal. A key aspect of this proposal will be testing these antibodies in combination to determine how many
receptors need to be targeted in order to get complete tumor regressions in animal models. Overall this work
will help us identify new therapeutic strategies for the treatment of brain cancer. Finally, we will also analyze
the way different receptors interact together in brain cancer cells.
Research achievements (from final report):
Aim 1) We have been successful in generating two antibodies directed to the IL-13Rα2 that block binding of
IL-13. During the past year we have been establishing if these antibodies can be used to deliver "payloads" to
cancer cells. Generation of antibodies directed to c-met has been challenging. However, we have managed to
produce 8 high affinity antibodies to c-met that bind the receptor on the cell surface and have characterized
their biological activity. A patent has been lodged and manuscript is being prepared. Aim 2) We have
concentrated on using the combination of EGFR and HGF (ligand for c-met) antibodies to treat glioma
xenografts. We have demonstrated that this combination is extremely efficacious, showing synergistic
antitumor activity in animal models. Aim 3) We have focused on the cross-talk between EGFRvIII, the most
common EGFR mutation in glioma, and c-met. We have conclusively demonstrated that expression of
EGFRvIII causes the ligand-independent of c-met leading to activation of Akt. While we are still elucidating
the mechanism involved our initial studies would suggest a direct interaction between EGFRvIII and c-met,
possibly involving the free N-terminal cysteine found in EGFRvIII (this work forms part of a new NH&MRC
application). We have also demonstrated that EGFRvIII is a very promiscuous receptor that activates several
tyrosine kinases on the cell surface including PDGFRβ. Finally, we have shown that Src interact with
EGFRvIII contributing to it tumorigenicity in cell lines and patient samples. Importantly, the combination of
Src and EGFR inhibitors is additive in glioma xenograft models.
Expected future outcomes:
The c-met antibodies have now been patented and are expected to generate significant commercial interest
Name of contact:
Terrance Johns
Email/Phone no. of contact:
Terry.johns@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436602
Start Year: 2007
CIA Name: A/Pr Tony Tiganis
End Year: 2009
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $513,947
Title of research award:
Tyrosine kinases and phosphatases in cell cycle checkpoint responsesTyrosine kinases and phosphatases in cell
cycle checkpoint responses
Lay Description (from application):
In order for an organism to grow and develop, the cells that make up the tissues and organs need to undergo a
process of cellular division, wherein individual cells grow and then divide into two cells. During this process
of cellular growth and division the entire genome needs to be duplicated (this occurs during S-phase) and then
divided equally into the two daughter cells. In S-phase several so-called 'checkpoint' mechanisms exist which
ensure that this occurs in an orderly and precise manner. The so-called 'DNA replication checkpoint' delays Sphase progression in response to 'replication stresses' that may otherwise cause DNA damage. Protein tyrosine
kinases (PTKs) are hyperactivated in many human solid tumours and blood malignancies contributing to varied
aspects of tumour progression. Our preliminary studies indicate that the inactivation of PTKs by protein
tyrosine phosphatases may be essential for the suppression of S-phase progression in response to replication
stress. Our goal is to understand the molecular mechanisms by which PTKs and tyrosine phosphatases
contribute to S-phase checkpoints. Our studies will provide important insights into DNA replication stressinduced checkpoint responses in mammals and identify unprecedented mechanisms by which hyperactivated
PTKs may contribute to tumour development.
Research achievements (from final report):
In order for an organism to grow and develop, the cells that make up the tissues and organs need to undergo a
process of cellular division, wherein individual cells grow and then divide into two cells. During this process of
cellular growth and division the entire genome needs to be replicated and divided equally into the two daughter
cells. Specific and intricate mechanisms known as 'checkpoints' exist to ensure that division occurs in timely
and precise manner and that the DNA is accurately replicated and segregated. In cancer, such mechanisms are
perturbed resulting in uncontrollable growth and tumour development. , Unscheduled activation of Src, JAK
and STAT3 contributes to the development of a wide range of human tumours including colon, breast &
pancreatic cancers. We have shown that Src, JAK and STAT3 are intimately associated with the regulation of
checkpoint responses during DNA replication. Our studies provide novel insight into mechanisms by which
Src, JAK and STAT3 hyperactivation may contribute to genomic instability and tumour development.
Expected future outcomes:
Our studies provide novel insight into mechanisms by which established oncoproteins contribute to genomic
instability and tumorigenicity.
Name of contact:
N/A
Email/Phone no. of contact:
Tony.Tiganis@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436614
Start Year: 2007
CIA Name: Prof David Jans
End Year: 2009
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $465,210
Title of research award:
The tumour cell-specific nuclear targeting properties of chicken anaemia virus VP-3: potential for anti-tumour
therapyThe tumour cell-specific nuclear targeting properties of chicken anaemia virus VP-3: potential for antitumour therapy
Lay Description (from application):
Current trends indicate that cancer will cause 40% of all deaths in Australia by 2012, meaning that new anticancer strategies are urgently required. Our proposal intends to examine the subcellular targeting abilities of
the unique tumour-cell specific agent apoptin (VP3 - viral protein 3), a small protein encoded by the genome of
the chicken anaemia virus. Using various strategies, we have identified part of the apoptin molecule that
confers efficient localisation in the nucleus of tumour cells, but not non-tumour cells. Our experimental
program intends to define this tumour cell-specific targeting signal in detail, and determine the molecular basis
of the differential subcellular localisation of apoptin in tumour compared to normal cells. This should
contribute fundamental new information regarding the differences between cancer and normal cells.
Additionally, we intend to optimise the targeting signal and perform initial experiments to test its efficacy in
targeting anti-tumour drugs to the nucleus of tumour cells. Our long-term aim is to use the apoptin tumour cellspecific nuclear targeting signal as part of modular constructs to combat cancer efficiently, and above all, with
minimal damage to normal cells and tissues.
Research achievements (from final report):
Our work as shown that VP3 (74-121) represents a tNTS (tumour cell specific nuclear targeting signal),
functional as an independent module for tumour-cell enhanced nuclear targeting, generally reliant upon the
same mechanisms of regulation as full length VP3. Likewise, we have also demonstrated that the kinetics of
nuclear accumulation of VP3 are accelerated in tumour compared to normal cells and the mobility of the
protein is also increased. We have shown through extensive analysis in isogenic cells that VP3 represents a
unique tNTS, a property that is not common to all nuclear localisation signal containing proteins. Finally we
have generated a number of modular recombinant proteins containing a drug binding moiety, cell-specific
ligand, endosomal escape domain and the VP3 tNTS, for the purposes of enhancing drug delivery to tumour
but not normal cells as potential novel chemotherapeutics. SIgnificantly, each module functions in the full
length protein as expected and the complexes accumulate strongly in the nucleus of tumour compared to
normal cells, highlighting their potential for further development. As current cemotherapeutic compounds have
significant side effects in terms of toxicity to the surrounding normal cells and ultimately the patient, these
constructs represent a great leap forward in the development of novel, safe and above all tumour-cell specific
drug delivery compounds.
Expected future outcomes:
The tNTS and the novel modular drug delivery constructs characterised/developed have significant benefits,
not only for the further development of safe and effective drugs to target cancer, but also as useful tools for the
investigation of fundamental differences in the nuclear transport systems of tumour versus normal cells.
Name of contact:
David A. Jans
Email/Phone no. of contact:
David.Jans@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436631
Start Year: 2007
CIA Name: Prof Matthew Wilce
End Year: 2012
Admin Inst: Monash University
Grant Type: NHMRC Research Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $749,275
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
A major research theme in my laboratory is understanding the basis of oligonucleotide recognition by RNAbinding proteins. Research in this area has lead to significant insights into the regulation of gene expression by
proteins that bind mRNA and regulate the expression inflammatory mediators, and, the molecular basis of the
signaling activation that occurs upon the detection of cytoplasmic RNA in viral invasion. I have also
investigated the molecular structures of important new drug targets in order to develop inhibitors to these
targets. This has lead to the development of new anti-Staphylococcus drugs and compounds that are able to
reduce the migration and proliferation of breast cancer cells..
Expected future outcomes:
A more complete understanding and characterisation of the protein/RNA complexes will lead to new means of
ameliorating some viral infections, and, new interventions in inflammatory disease. The new therapeutics will
lead to control of multidrug resistant bacterial infection and improved prognosis for breast cancer patients.
Name of contact:
Matthew Wilce
Email/Phone no. of contact:
Matthew.wilce@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436636
Start Year: 2007
CIA Name: Prof Christina Mitchell
End Year: 2009
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $549,197
Title of research award:
The role of the 72 kDa inositol polyphosphate 5-phosphatase in cellular function.The role of the 72 kDa
inositol polyphosphate 5-phosphatase in cellular function.
Lay Description (from application):
Cells respond to external signals and the environment to undergo cell growth, secretion and/or other specialized
functions including control of cell death and/or cell size. We have identified a new enzyme (72kDa 5phosphatase) which resides inside the cell and regulates signals generated by an enzyme called PI3-kinase.
Two of the PI3-kinase signals have been demonstrated to regulate the activity of an oncogene involved in
breast and ovarian cancer. We aim to determine the specific role each of these PI3-kinase signals plays in the
activation of the oncogene. In addition the levels of the 72kDa enzyme is altered in some cervical and
lymphoma cancers. We will image live cells containing specific fluorescent probes under different conditions
and study the activation and location of these probes in order to understand how different PI3-kinase signals
are regulated in time and space. In addition to regulating signals that are involved in cancer, PI3-kinase
controls signals that are important for proper immune function. Phagocytosis is a biological process where
specialised immune cells (macrophages) take up and remove harmful particles such as bacteria or tumour cells
from the circulation. This process depends on PI3-kinase and the signals it produces. We will determine
whether the 72 kDa enzyme, which is expressed in macrophages, plays a role in regulating these signals during
phagocytosis. We have shown that the 72 kDa enzyme can interact with several different proteins which may
affect its location and activity within the cell. We will examine the effect of these interactions on the PI3kinase signals which are involved in cell survival and immune responses. We will study the function of the
enzyme in the intact animal by producing mice which lack this enzyme. Given the possible role of this enzyme
in cancer, these mice will be examined for their susceptibility to develop tumours.
Research achievements (from final report):
This grant has investigated the function of a novel gene Innp5e, which encodes for an enzyme that regulates an
intracellular signal, called PtdIns(3,4,5)P3, which is generated when growth factors or hormones stimulate
cells. Inpp5e, also called the 72 kDa inositol polyphosphate 5-phosphatase degrades PtdIns(3,4,5)P3 signals
that are generated by the phosphoinositide 3-kinase, to regulate a signalling cascade that plays a fundamental
role in many cellular events including cell division and cell death. We have determined the function of the 72
kDa 5-phosphatase by generating cell lines with reduced expression of this enzyme, and also by generating
mice which lack the 72 kDa 5phosphatase. These studies demonstrate the 72 kDa 5-phosphatase is essential for
early human development and mice which lack this enzyme development multiple abnormalities including
abnormal brain development and polycystic kidneys.
Expected future outcomes:
We have generated mice with gene targetted deletion of inpp5e and we will determine the molecular basis of
the phenotype which exhibits embryonic lethality and developmental abnormalities.
Name of contact:
Christina Mitchell
Email/Phone no. of contact:
Christina.mitchell@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436638
CIA Name: Prof Christina Mitchell
Admin Inst: Monash University
Main RFCD: Oncology and Carcinogenesis
Total funding: $533,828
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
The role of PIPP in cell polarization and proliferation.The role of PIPP in cell polarization and proliferation.
Lay Description (from application):
Normally cells only divide when they receive a stimulus such as from a hormone or growth factor. Upon
stimulation, a series of signals are generated inside the cell which lead to cell division and development. One of
the signaling pathways which responds to growth factor stimulation is the PI3-kinase pathway. This pathway
has been implicated in many different human cancers which occur when cells divide uncontrollably and invade
into the surrounding tissues. Following growth factor stimulation, PI3-kinase generates a molecule known as
PtdIns(3,4,5)P3 which leads to the activation of many proteins in the signaling pathway. All cells which have
PI3-kinase also have enzymes which act to switch off the signals generated by PI3-kinase and thus may play a
role in preventing cancer and regulating cell development. We have identified a new enzyme known as PIPP
and have shown that it acts to switch off the signals generated by PI3-kinase. We plan to investigate the role of
PIPP by increasing or decreasing the amount of PIPP in cells and analysing the effects on cell growth and
development. We have also identified a number of proteins which bind to PIPP and we will investigate the role
these proteins play in regulating cell signaling. In addition, we plan to characterize the function of PIPP in a
whole animal by generating mice which lack PIPP (knockout mice) and assessing the effects on development
and cancer.
Research achievements (from final report):
, Cancer occurs when cells divide uncontrollably and invade into surrounding tissues. Normally, cells only
divide when they receive an external stimulus such as a growth factor or hormone which generates a series of
signals inside the cell to promote cell division. One of the signalling systems inside the cell which responds to
growth factor stimulation is the PI3-kinase pathway which has been strongly implicated in many different
human cancers. There are three classes of PI3-kinase and each class generates a specific set of
phospholipids.One of the phospholipids generated by class I PI3-kinase is known PIP3. PI3-kinase generates
PIP3 which is able to activate a protein known as Akt leading to cellular transformation. , All cells which
contain PI3-kinase also have enzymes which act to oppose and switch off PI3-kinase generated signals. We
have identified a novel enzyme known as PIPP and shown that it specifically switches off PI3-kinase signals by
degrading PIP3. Over-expression of PIPP in cells reduces the levels of PIP3 leading to decreased activation of
Akt and subsequently inhibits PI3-kinase induced cellular transformation. This study has demonstrated that
PIP3 is an essential component of PI3-kinase-mediated carcinogenesis and that the inability to generate PIP3
abolishes carcinogenic potential.
Expected future outcomes:
We have generated mice with targeted deletion of PIPP and will characterise the phenotype of these mice.
Name of contact:
Christina Mitchell
Email/Phone no. of contact:
christina.mitchell@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436691
Start Year: 2007
CIA Name: Prof Paul Hertzog
End Year: 2011
Admin Inst: Monash University
Grant Type: Established Career Fellowships
Main RFCD: Immunology not elsewhere classified
Total funding: $768,745
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I work on the molecular mechanisms of innate immunity. Priorities of my work are the immune response to
pathogens such as viruses and bacteria and to cancer.
Research achievements (from final report):
This NHMRC fellowship supported the research career of scientist, Professor Paul Hertzog. Prof Hertzog has
been supported as a research fellow by the NHMRC since 1996 and he has continued to perform worldstandard medical and health science research in the fields of innate immunity and infectious disease between
2007 and 2011. Prof Hertzog's specialty field are interferons, which are molecules of the innate immune system
which direct immune responses to infection and modulate inflammation in diseases such as cancer. In the past
five years, Prof Hertzog's signficant achievements have included: , 1) Developing the INTERFEROME
database, a computational tool which allows identification of interferon gene signatures from molecular
information generated by high-throughput expression technologies. In 2012, INTERFEROME v2.0 was
released and it is an invaluable tool for infection and immunity researchers. , 2) Identifying an innate immune
response associated with metastatis of breast cancer to bones using the INTERFEROME database. This finding
has real clinical significance as it points to new therapies which may prevent breast cancer metastatising. , 3)
Discovering and characterising a unique interferon which is expressed exclusively in the female reproductive
tract, and which Prof Hertzog's research team have shown has a vital role in combatting infections. , 4)
Characterising the molecular pathways through which interferons signal their messages to cells. Studying the
interferon receptor, Prof Hertzog's team identified previously unknown ways by which interferons bind to cells,
providing important insights into basic immunology and changing how interferon scientists think about the
molecular processes which lead to inflammation.
Expected future outcomes:
In 2012-2016, Prof Hertzog will continue his breakthrough research into innate immunity, cancer and
infectious disease. Based on the achievements of 2007-2011, his team will investigate targeted therapies for
metastatic breast cancer and the role of a female reproductive tract interferon in preventing infections with
herpes simplex virus and Chlamydia.
Name of contact:
Professor Paul Hertzog
Email/Phone no. of contact:
Paul.Hertzog@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436774
CIA Name: A/Pr Martin Lackmann
Admin Inst: Monash University
Main RFCD: Oncology and Carcinogenesis
Total funding: $303,828
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
The role of protein tyrosine phosphatases regulating Eph RTK-signalling and modulating invasive tumour cell
properties.The role of protein tyrosine phosphatases regulating Eph RTK-signalling and modulating invasive
tumour cell properties.
Lay Description (from application):
The Ephs and interacting ephrins are proteins on the cell surface, which enable orientation of cells that move
within the body tissues and organs, but also in tumours. Eph proteins have tyrosine kinase enzyme activity that
becomes active after binding ephrins on neighbouring cells. Once active, they instruct these cells to change
their shape and their adhesion to the substratum or between each other, and to become more motile. In adult
organisms Ephs and ephrins are low in most cells, but they re-appear in many tumors. For example, when
normal cells in the skin (melanocytes) become tumor cells, they often will have Ephs and ephrins on their
surface. It is believed that these proteins will now affect if these melanoma cells will migrate and to which
locations within the body. In our studies we will examine what controls the activity of Eph proteins. In
particular, a class of enzymes called tyrosine phosphatases are known to regulate the function of tyrosine
kinase receptors, however it is not clear which particular phosphatase regulates EphA3, the focus of our
studies. We will find out, which set of phosphatases regulates EphA3 function and whether exposure to
oxidative conditions, such as UV radiation, also activates Ephs and instructs tumour cells to become more
motile and to invade other areas of the body. The understanding of this mechanism will help to understand the
cause of cancers such as melanoma and might offer possibilities to optimise new strategies for its treatment.
Research achievements (from final report):
The EphA3 receptor tyrosine kinase belongs to a family of enzymes on cell surfaces functioning as 'global
positioning system' to ensures correct cell positioning during formation of tissues and organs. The same
function also contributes to tumour spreading and in several cancer types EphA3 is regarded as prominent
cancer gene. Ephs function is controlled by phosphatases, a family of enzymes that reverse the biochemical
signal of protein kinase receptors such as Ephs., During the course of this grant we identified specific
phosphatases which during the assembly of tissues from cells control the function of Ephs and elaborated the
molecular mechanism underlying this process. We discovered the PTP1B phosphatase as essential component
of a molecular switch that determines if cells adhere or segregate to/from each other, a switch of critical
importance for understanding of cell interactions during tumour growth and the potential as target for
therapeutic intervention. Our findings and their implications have been published in refereed international
journals and provided the basis for ongoing studies pursuing development of targeted anti-cancer reagents
enhancing the action of PTP's to inactivate oncogenic Eph function. This continuing research is now funded by
an NH&MRC program grant (colon cancer), by Cancer Australia/ Prostate Cancer Foundation (prostate
cancer). In addition, studies with collaborators in Canada and Germany, to unravel the role of this Eph/PTP
switch during blood vessel formation are funded by the Human Frontiers Science Organisation.
Expected future outcomes:
Our identification of the critical enzymes that control the function of a prominent cancer gene provides the
basis for development of therapeutics normalising uncontrolled tyrosine kinase function in diseases such as
chronic inflammation and cancer. Proof of concept studies with these reagents will reveal the therapeutic
potential of this strategy.
Name of contact:
Martin Lackmann
Email/Phone no. of contact:
NHMRC Research Achievements - SUMMARY
Martin.Lackmann@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436814
CIA Name: Prof Bryan Williams
Admin Inst: Monash University
Main RFCD: Cellular Immunology
Total funding: $531,697
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Role of PLZF in regulating the Interferon responseRole of PLZF in regulating the Interferon response
Lay Description (from application):
The Interferon (IFN) pathway is essential for immune defense against pathogens in vertebrates. IFNs both
protect and alert cells about viral, bacterial, and other immune assaults and promote a cellular antiviral state,
reduce proliferation, or induce apoptosis depending on the cell type and environment. Based on these
properties, IFNs have been used clinically against a variety of diseases including viral infections,
immunomodulatory disorders and hematologic and solid tumors including renal cell carcinoma. However, the
factors determining outcome of IFN treatment, remain to be determined. We have identified a subset of
interferon stimulated genes whose sustained expression was found to correlate with heightened antiviral
sensitivity of renal cell carcinoma cell lines to IFN. Many of these genes were found to have binding sites for
the transcriptional repressor promyleocytic zinc finger protein (PLZF). PLZF was first identified in a subset of
Acute Promyelocytic Leukemia patients and is involved in maintenance of erythroid lineage stem cells and
spermatogonial stem cells in male mice. PLZF has not previously been implicated in the IFN response.
Accordingly, we investigated the expression of interferon stimulated genes and showed that increased
expression of immune related genes depends on PLZF expression. PLZF was also found to directly associate
with binding sites in promoters of interferon stimulated genes and that this requires histone deacetylation.
Thus, we uncovered a novel function for PLZF in enhancement of IFN associated gene expression. We propose
to test the hypothesis that PLZF is an essential component of the IFN response. As a corollary, we will also test
whether PLZF expression can be linked to IFN responsiveness in renal cell carcinoma. These studies will
establish the role of PLZF in the IFN response and define its utility in predicting IFN responsiveness in
therapeutic applications.
Research achievements (from final report):
We have discovered that the transcription factor promyelocytic leukemia zinc finger protein (PLZF) plays an
important role in the immune response mediated by interferon. Interferon was shown to stimulate an
association between PLZF and cofactors to switch on several key interferon-stimulated genes, including those
involved in protection against viral infections. Mice lacking the gene that codes for PLZF were found to be
more susceptible to infection with viruses. Moreover, the activity of natural killer cells, which play an
important role in the innate immune response, was impaired in mice lacking PLZF., This research provides
new insights into the mechanisms regulating the action of interferons, and demonstrates that PLZF is an
important factor in the innate immune response. The findings were published in the high impact journal
Immunity (Xu et al. 2009, Immunity 30:802-816), and were accompanied by a preview article discussing the
significance of the research (Ozato).
Expected future outcomes:
PLZF is an important factor in the innate immune response, and therefore could be used as a possible target for
anti-viral and anti-tumour therapeutics, resulting in the development of novel drugs to treat viral infections and
cancers.
Name of contact:
Professor Bryan Williams
Email/Phone no. of contact:
Bryan.Williams@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 459405
Start Year: 2007
CIA Name: Prof Peter Currie
End Year: 2009
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cell Development (incl. Cell Division and Apoptosis)
Total funding: $496,447
Title of research award:
The role of scube genes in hedgehog signal transductionThe role of scube genes in hedgehog signal
transduction
Lay Description (from application):
Cancer often results form the miss-regulation and/or mutation of genes that control tissue formation in the
developing embryo. Particular sets of genes combine to form a signal transduction pathway that coordinates
the cell's response to its environment during the course of normal fetal growth. One such pathway is called the
Hedgehog signal transduction pathway which has been shown to coordinated cell division and patterning
within malignant and normal tissues. Genes encoding components of this pathway are mutated in the most
common forms of human cancers. Understanding how this pathway is regulated is critical to designing
strategies to treat the onset and progression of these cancers. The studies outlined in this grant plan to study a
new component of this pathway that we have identified in our laboratory, in an easy to study vertebrate model,
the zebrafish embryo. We plan to study how this class of proteins, termed scube proteins, acts to control
activation of the pathway. We hope this will lead to a fuller understanding of this process, and at the same time
help understand the nature of the end result of the patterning process within the muscle cells that we are
studying
Research achievements (from final report):
This project focused on understanding the role of particular genes that we had identified that disrupted
zebrafish development and we could show altered Hedgehog signal transduction, one of the major signaling
pathways that controls development of the organism, and has been widely implicated in cancer. Previous work
had implicated the scube2 gene in Hedgehog signal transduction, although the phenotype of loss of function of
scube2 was mild compared to other mutations that disrupted signaling in the Hedgehog pathway. The premise
of this grant was that other orthologues of scube2 could compensate for its function in vivo, and that by
studying these genes and knocking down the function of all scube genes at once we would learn more about the
function of this mysterious class of protein in Hedgehog signal transduction. This study to identified how other
scube genes in the zebrafish genome functioned in concert to regulate Hedgehog signal transduction in
zebrafish, an revealled they are essential for this major developmental and disease causing sugnalling pathway.
Part of this process was also to generate antibodies to scube2 and use these reagents to unravel the mechanistic
basis of Scube2 function with in the cell.
Expected future outcomes:
We aim to manipulate the signalling through this class of molecule to regulate the hedgehog signalling pathway
Name of contact:
Peter Currie
Email/Phone no. of contact:
peter.currie@armi.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 461208
Start Year: 2007
CIA Name: Prof Graham Lieschke
End Year: 2012
Admin Inst: Monash University
Grant Type: NHMRC Research Fellowships
Main RFCD: Genetic Development (incl. Sex Determination)
Total funding: $809,275
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a cell-development biologist using genetic approaches in the model vertebrate zebrafish to study the
regulation of myeloid blood cell development. My laboratory haematology research is in basic science and
biology of haemopoiesism but is closely rel
Research achievements (from final report):
White blood cells, which include macrophages and neutrophils, are important in host defence. When white
blood cells go wrong, diseases result. Myelodysplasia and leukaemia are due to faulty cell growth and
development, and inflammatory and autoimmune disorders are due to defective regulation of white blood cell
function. Prof Lieschke is a clinical haematologist and scientific researcher who leads a research group
studying the development and function of white blood cells, particularly neutrophils and macrophages, in
normal physiology and disease. By studying zebrafish with genetic defects in blood cell development, he has
defined new roles for several genes in blood cell development. Several of these genes have recently been
implicated in myelodysplasia and leukemia. This work is providing insights in to the causes of these serious
disorders and suggests possible new treatment targets. Prof Lieschke's lab has made zebrafish engineered to
express transgenes in specific white blood cell types, enabling them to be observed in action in the whole
animal and permitting their function to be experimentally modified and tested. These approaches have revealed
new insights into how the inflammatory response is initiated and regulated after wounding. One study
particularly has identified a new mechanism that regulates how vigorously inflammation is initiated. Other
work has provided new insights into how white blood cells ptoect against bacterial and fungal infection. New,
unexpected interactions between neutrophils and macrophages have been observed that open up new
possibilities for treating inflammatory and infective disorders.
Expected future outcomes:
Better understanding of the genetic causes of myelodysplasia and leukaemia, these studies will suggest new
diagnostic tests and may identify new targets for treating these diseases. Knowing how inflammation is turned
on and off will point to new anti-inflammatory treatments approaches. Seeing how white blood cells and
micro-organisms interact will point to novel ways of treating infections.
Name of contact:
Graham Lieschke
Email/Phone no. of contact:
Graham.Lieschke@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 465121
CIA Name: A/Pr Caroline Gargett
Admin Inst: Monash University
Main RFCD: Obstetrics and Gynaecology
Total funding: $471,059
Start Year: 2007
End Year: 2011
Grant Type: Career Development Fellowships
Title of research award:
Endometrial stem cells in womens health, disease and tissue engineeringEndometrial stem cells in womens
health, disease and tissue engineering
Lay Description (from application):
Not Available
Research achievements (from final report):
This research has made major contributions in advancing the emerging research field of endometrial stem cells,
providing conclusive evidence for the first time of the existence of epithelial progenitor cell and mesenchymal
stem cell (MSC) populations in the highly regenerative lining of the uterus. Specific markers have been
identified that purify endometrial MSC. These showed that endometrial MSC are located around blood vessels
throughout the endometrium, indicating they are shed into menstrual blood. Several candidate markers for
identifying the epithelial progenitor population were also discovered, enabling us to gain new insights into
gynaecological diseases associated with abnormal endometrial proliferation. For example we have
demonstrated for the first time that endometriosis (growth of endometrium outside the uterus) develops from
the backflow of endometrial stem/progenitor cells into the pelvic cavity in menstrual debris, proving an 86 year
old hypothesis. Cancer stem cells were identified in human endometrial cancer by their functional properties. A
novel model was developed for studying the fetal development of uterine epithelium using human embryonic
stem cells., Since endometrial MSC are obtained with relative ease by office biopsy procedure we commenced
a project examining their utility as a cell-based therapy for treating pelvic organ prolapse, a major hidden
epidemic affecting 25% of women. Simple methods for isolating endometrial MSC and producing large
numbers of cells for transplantation have been developed and are being refined under Good Manufacturing
Practice guidelines for translation into the clinic. Working with CSIRO, new material scaffolds and preclinical
animal models are being developed to deliver these cells for repair of the vaginal walls.
Expected future outcomes:
The knowledge generated on endometrial stem/progenitor cells may lead to a new generation of non-hormonal
medical treatments targeting these cells that will improve the health of the many women suffering
endometriosis. Cell-based therapies using endometrial MSC may become available to repair damaged pelvic
support structures for women with pelvic organ prolapse.
Name of contact:
Caroline Gargett
Email/Phone no. of contact:
caroline.gargett@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 465207
Start Year: 2008
CIA Name: Dr Susan Lee
End Year: 2009
Admin Inst: Monash University
Grant Type: SRDC - People
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $137,000
Title of research award:
Developing and measuring palliative care decision making skillDeveloping and measuring palliative care
decision making skill
Lay Description (from application):
Relationships and communication skills that health professionals develop with patients are critical to patient
involvement in decision making. This project will build on previous decision making research and the
development of palliative care education for undergraduate students. The key components of successful
decision making skills will be investigated and an education program and skill measures for undergraduate and
postgraduate health professional students will be developed and pilot tested.
Research achievements (from final report):
There is considerable public attention on the need for people to work with health professionals in developing
plans for the end of their lives. In order to assist develop these plans, health professionals need to be able to
engage people in difficult conversations. However, few health professionals are educationally prepared in the
skills required to involve patients in these types of decisions. This research achieved an eight category
assessment tool for measuring the skill associated with involving patients and their families in care decisions.
The tool has been trialled in a workshop of experienced health professionals and educators and has received
encouraging feedback. Further testing of the tool in student learning and clinical environments is planned. In
addition, the study has developed a series of teaching and learning activities that specifically relate to the
development of these skills. , The fellowship also enabled me develop important skills related to developing
and managing research programs. For example, I attended classes in research methodologies that I had not
developed during my PhD. In addition, I participated in workshops on research leadership, particularly in
developing and managing budgets, collaboration and governance of research. In addition, to complement the
particular study I was engaged with, I completed training in advance care planning in order to examine the
skills required in this significant area of decision making and also spent time with complementary research
team who were developing educational programs in palliative care.
Expected future outcomes:
The teaching and learning activities and assessment tool related to involving patients in decisions about their
care will be incorporated in to the core palliative care curriculum for undergraduate students.
Name of contact:
Dr Susan Lee
Email/Phone no. of contact:
Susan.Lee@monash.edu
lee
NHMRC Research Achievements - SUMMARY
Grant ID: 487907
CIA Name: Prof Ian Davis
Admin Inst: Monash University
Main RFCD: Oncology and Carcinogenesis
Total funding: $176,116
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Research Fellowships
Title of research award:
Practitioner FellowshipPractitioner Fellowship
Lay Description (from application):
I am a medical oncologist and tumour immunologist, dedicated to basic and translational clinical research
particularly in the field of urological cancer and also in melanoma.
Research achievements (from final report):
This Fellowship supported the establishment of a comprehensive program of laboratory and clinical research in
cancers of the urinary tract (prostate, kidney, bladder). It assisted setting up a broad network of collaborations
in Australia and internationally; collection of cancer and normal tissue for laboratory studies; collection of
clinical information including setting up a database in kidney cancer and a prostate cancer registry; laboratory
studies of prostate, kidney and bladder cancer; development of new treatments and conduct of clinical trials;
and support for multiple researchers. As a result, Australia now has a new cooperative clinical trials group in
these cancers that has a strong international reputation (ANZUP Cancer Trials Group; www.anzup.org.au). The
tissue collection provides a strong base for our research and that of other researchers. The databases are already
bearing fruit in terms of helping us understand how these cancers are treated in the general community and
where the gaps are. the laboratory studies have given us new insight into how the immune system interacts with
these cancers, particularly prostate cancer. New clinical trials have come to Australia as a result of all this.
Opportunities for clinicians to work in the lab have also been made available and many of these people are now
going on to independent research careers of their own.
Expected future outcomes:
These resources and discoveries have allowed better understanding of the events underlying cancers of the
urinary tract, and in turn these have pointed the way to new areas of research and new treatments that are
coming to the Australian community.
Name of contact:
Ian Davis
Email/Phone no. of contact:
ian.davis@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 487910
CIA Name: A/Pr Margaret Hibbs
Admin Inst: Monash University
Main RFCD: Respiratory Diseases
Total funding: $535,333
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
The role of Src family tyrosine kinases in inflammatory lung disease and cancerThe role of Src family tyrosine
kinases in inflammatory lung disease and cancer
Lay Description (from application):
We aim to learn why some people develop COPD, a serious lung disease, and adenocarcinoma, a common fatal
lung cancer. COPD is mostly caused by cigarette smoke which induces lung inflammation. Lung inflammation,
which involves macrophage activation, is a major cancer risk. Macrophages can destroy lung tissue, and they
may promote cancer development. We will study the role of Src kinases, which can regulate macrophage
activation, which may lead to new treatments for these diseases.
Research achievements (from final report):
Chronic obstructive pulmonary disease (COPD) is a serious inflammatory lung disease that afflicts over 1
million people in Australia. COPD is almost exclusively caused by cigarette smoking, and macrophage-rich
inflammation is a hallmark feature. Macrophages can destroy lung tissue and promote cancer development.
During the course of this project, we have identified macrophage subpopulations that are associated with acute
and chronic lung inflammation. Further characterisation of these subpopulations may identify therapeutic
targets that could yield novel intervention strategies.
Expected future outcomes:
The current treatments for COPD are largely non-specific and ineffective. By identifying and characterising
pathogenic macrophage subpopulations that are associated with chronic inflammatory diseases and lung
cancer, we hope to gain a better understanding of how to selectively targeting them without paralyzing
macrophage-dependent innate immune defenses and tissue homeostasis.
Name of contact:
Margaret Hibbs
Email/Phone no. of contact:
Margaret.Hibbs@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 490938
CIA Name: Prof Susan Davis
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $690,082
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Research Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am an academic endocrinologist and clinician. I lead a large research program that investigates the links
between hormones and diseases of ageing in women. Thus my research program addresses the contribution of
changes in adrenal and ovarian steroids in
Research achievements (from final report):
I lead and published the largest and longest efficacy and safety study of the use of testosterone therapy for
women, a placebo-controlled RCT of 800 women recruited across 3 continents (NEJM Davis et al 2008). I
established the BUPA Health and Well Being After Breast Cancer Study which recruited 1684 women within
their 1st year of breast cancer (BC) diagnosis 2004-6. This is the largest longitudinal study to report on factors
substantially impacting BC survivors, ranging from sexual dysfunction through to determinants of wellbeing
and patterns of adherence to endocrine therapy. This study has resulted in 18 publications to date and a number
of manuscripts in preparation.My group has reported on the prevalence, incidence and risk factors for urinary
incontinence (UI) in women and the incidence of fecal incontinence in women. I conducted the first study of
UI in young women who have never been pregnant and showed that 1 in8 such women have UI. I developed
the PROSPECT tool for health practitioners to identify the women 70 + years most likely to have
osteroporosis/fracture. I also developed and validated a sexual function questionnaire now used by researchers,
and a menopause stageing questionnaire. I have completed several studies exploring the role of sex steroids on
cognitive performance in women. ?????
Expected future outcomes:
To document the prevalence and severity of menopausal symptoms and of depression in Australian women at
midlife, their use of prescribed and complimentary and alternative therapies, plus a range of other studies of
midlife women's health.
Name of contact:
Susan Davis
Email/Phone no. of contact:
Susan.Davis@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 490956
Start Year: 2008
CIA Name: Dr Brendan Jenkins
End Year: 2008
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $174,800
Title of research award:
Cross-talk between cytokine and pathogen recognition receptor networks in the pathogenesis of gastric
cancerCross-talk between cytokine and pathogen recognition receptor networks in the pathogenesis of gastric
cancer
Lay Description (from application):
Stomach cancer is the second most common cause of cancer-related deaths worldwide, and results in the yearly
death of several thousand people in Australia alone. We have discovered a specific mutation in a gene called
gp130 that results in the formation of gastritis and stomach cancer in mice. We are now aiming to understand
the exact molecular events by which this mutation results in chronic inflammation and the subsequent
uncontrolled growth of epithelial cells that line the stomach wall.
Research achievements (from final report):
Studying an altered form of a molecule called gp130 which is in every cell of the body, our aim is to learn
more about how and why inflammation disorders and cancers develop. We have discovered a specific mutation
in gp130 that leads to over-activation of gp130 and results in the formation of stomach inflammation (gastritis)
and cancer in mice. As an example of the significance of these findings to human health, stomach cancer is the
second most common cause of cancer-related deaths worldwide, and the molecular mechanisms by which
chronic stomach inflammation and cancer develop in some people are unknown. , One of the key achievements
of our work has been identifying that over-activation of gp130 causes over-activation of a group of proteins on
cells called toll-like receptors (TLRs). These TLRs play a crucial role in recognizing bacteria and other microorganisms upon which the TLRs then regulate the inflammatory response. Hence, our results identify for the
first time that deregulated interactions between stomach micro-organisms and TLRs can lead to chronic
inflammation and the subsequent uncontrolled growth of epithelial cells that line the stomach wall., We also
note that considering the common molecular and cellular events that contribute to the inflammatory program,
importantly our research findings will extend to further define the mechanisms by which uncontrolled
inflammation can result from deregulated interactions between micro-organisms and TLRs in other cancers,
such as the colon which are also characterized by gp130 over-activation.
Expected future outcomes:
Understanding how TLRs are regulated, and the cell/tissue-specific context in which this occurs, will
ultimately identify novel biomarkers to screen/detect disease at an early stage, as well as provide the molecular
basis on which to design next-generation therapeutic strategies and reagents to prevent inflammation and
cancer.
Name of contact:
Brendan Jenkins
Email/Phone no. of contact:
brendan.jenkins@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490977
CIA Name: Prof Magdalena Plebanski
Admin Inst: Monash University
Main RFCD: Cellular Immunology
Total funding: $690,502
Start Year: 2008
End Year: 2013
Grant Type: NHMRC Research Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I study basic mechanisms of the interaction of pathogens and particles with the immune system, to gain insight
into mechanisms of adjuvanticity, immune evasion and generally immuno-modulation. With this specific
insight I further pursue the development of
Research achievements (from final report):
Defined the new ways in which tiny particles the size of viruses and bacteria interact with the immune system,
changing thus the dogma that breathing in particles is always bad for the health of the lung, and showing that it
is possible for nanotechnology to deliver new therapeutics to prevent asthma, as well as to enable the design of
outstanding vaccines (thus far proven in animal models) against major diseases such as cancer and malaria.
Expected future outcomes:
A clincial trial of our nanovaccines is planned to test their safety and potency in humans with cancer. We will
also define the specific molecular elements which have enabled ceratin nanoparticles to provide a new range of
beneficial lung effects, to further support practical tranlation of our findings.
Name of contact:
Prof. Magdalena Plebanski
Email/Phone no. of contact:
magdalena.plebanski@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491029
Start Year: 2008
CIA Name: Prof Christina Mitchell
End Year: 2010
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $557,939
Title of research award:
Regulation of PtdIns(3,4)P2 signalling by inositol polyphosphate 4-phosphatase-1Regulation of PtdIns(3,4)P2
signalling by inositol polyphosphate 4-phosphatase-1
Lay Description (from application):
Normally cells only divide when they receive a stimulus such as from a hormone or growth factor. One of the
signaling pathways which responds to growth factor stimulation is the PI3-kinase pathway. This pathway has
been implicated in many different human cancers which occur when cells divide uncontrollably and invade into
the surrounding tissues. We have idenitified a novel enzyme called the inositol polyphosphate 4-phosphatase
that appears to regulate cell proliferation and differentiation.
Research achievements (from final report):
Normal cells only divide when they recieve a stimulus such as a hormone or growth factor. In contrast cancer
cells divide and spread as they have lost these normal constraints. We have identified and characterised an
enzyme within many human cells which functions to control cell proliferation and when lost from the cell we
have demonstrated this results in increased cell proliferation, a reduction in cell death and also an increased
propensity for these enzyme-deficient cells to form tumours. This enzyme (inositol polyphosphate 4phosphatase-1) terminates a signalling pathway (PI3-kinase) within cells that is activated by growth factors or
hormones and when 4-phosphatase-1 is lost this results in continual activation of the PI3-kinase pathway
leading to accelerated cell growth. This study provides the first evidence, to our knowledge, that 4phosphatase-1 controls the activation of the PI3K signalling and thereby cell proliferation, survival and
tumorigenesis.
Expected future outcomes:
We will investigate in future studies in human tumours and in mice which are deficient in 4-phosphatase-1 if
this leads to a cancer predisposition.
Name of contact:
Christina Mitchell
Email/Phone no. of contact:
Christina.mitchell@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491055
Start Year: 2008
CIA Name: Prof David Jans
End Year: 2010
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $495,830
Title of research award:
Negative regulators of nuclear import; potential links to cancerNegative regulators of nuclear import; potential
links to cancer
Lay Description (from application):
Trafficking of proteins into the nucleus is critical to mammalian cell function, relating strongly to
developmental processes and cancer. We have identified a new class of molecule - negative regulators of
nuclear import - that function to prevent entry into the nucleus of key regulators of the cell cycle/apoptosis, and
have a potential link thereby to cancer. We propose to determine their mechanism of action, modulation by
cellular signals, and how important this is to cell function/cancer.
Research achievements (from final report):
We established for the first time that nuclear import of proteins relevant to cancer and viral disease can be
negatively regulated by a specific class of proteins - NRNIs (negative regulators of nuclear import). The results
have relevance to new approaches to tackle cancer and viral disease.
Expected future outcomes:
We will pursue the findings here to advance our understanding of cancer and viral disease, and proceed
towards therapeutic approaches.
Name of contact:
David Jans
Email/Phone no. of contact:
david.jans@Monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491087
Start Year: 2008
CIA Name: Dr Heather Verkade
End Year: 2011
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Genetic Development (incl. Sex Determination)
Total funding: $535,333
Title of research award:
A fluorescent zebrafish model of endodermal cell migration.A fluorescent zebrafish model of endodermal cell
migration.
Lay Description (from application):
The most catastrophic event in cancer progression is when individual cancer cells move to other areas of the
body and develop into secondary tumours. This very complex process shows striking similarities to cell
movements during embryogenesis. In this project, we use a model system, the zebrafish, to analyse how cells
move during embryogenesis. We will determine the genes required for cell movements in the zebrafish
embryo, so we can find the corresponding genes in human cancers.
Research achievements (from final report):
We have discovered that the early embryonic gut precursor cells in the zebrafish follow a chemical pathway
towards the midline of the embryo to form the future gut.
Expected future outcomes:
This increases our understanding of how embryonic cells move, which relates to the same pathways that cancer
cells use to move.
Name of contact:
Heather Verkade
Email/Phone no. of contact:
heather.verkade@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491088
Start Year: 2008
CIA Name: Prof Robert Medcalf
End Year: 2012
Admin Inst: Monash University
Grant Type: NHMRC Research Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $630,275
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a cell-molecular biologist studying the role and regulation of the plasminogen activating (fibrinolytic)
system in health and disease. My recent studies have defined a novel role for tissue-type plasminogen activator
in the central nervous system and
Research achievements (from final report):
I directed a number of projects aimed at understanding how the plasminogen activating system modulates
blood brain barrier permeability (BBB) and other aspects of brain function with a view to gaining insights
towards novel approaches for patients with ischaemic stroke or traumatic brain injury (TBI). Most of our effort
was directed towards the role of tissue-type plasminogen activator (t-PA). We found that brain t-PA activity is
significantly modulated following stroke and TBI and in various neurodegenerative conditions. We identified a
number of candidate targets that reduce the extent of t-PA mediated opening of the BBB following TBI
including MMP-3, and LDL receptor blocking agents. We also identified the Rho kinase pathway in astrocytes
was activated upon treatment with t-PA and that inhibition of this pathway attenuated the action of t-PA on
BBB permeability. These drugs have a potential for patients not only with brain trauma but also with patients
with ischaemic stroke. Another major achievement was our discovery that the fibrinolytic system is not driven
necessarily by fibrin formation, but by the formation of misfolded/aggregated proteins in general, in a process
we called "nucleocytoplasmic coagulation (NCC)" that occurs following cell death. These aggregates are
recognised by plasminogen and t-PA and are removed by plasmin. We also discovered that this non-fibrin
clearance mechanism also engages the innate immune system.Our work on the post transcriptional regulation
of the plasminogen activator inhibitor-2 (PAI-2) mRNA lead to the identification of a multi-component mRNA
destabilising motif in this transcript.
Expected future outcomes:
We intend to develop the use of MMP-3 inhibitors, LDL receptor blocking agents and Rho kinase inhibitors as
novel treatments for TBI and ischaemic stroke. We will also further explore the role and significance of NCC
in biology and pathology, particularly in relation to its effect on the innate immune response.
Name of contact:
Robert Medcalf
Email/Phone no. of contact:
robert.medcalf@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491092
CIA Name: Prof Bryan Williams
Admin Inst: Monash University
Main RFCD: Genetics not elsewhere classified
Total funding: $571,311
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Functional analysis of relapse predictive genes in Wilms tumourFunctional analysis of relapse predictive genes
in Wilms tumour
Lay Description (from application):
Wilms tumor is a paediatric kidney cancer, the most common abdominal tumour seen in children. About 20%
of Wilms tumour patients have relapsing fatal tumours. We have found two genes that mark tumours which
relapse: C/EBPB and CLK1. Characterization of C/EBPB and CLK1 will yield new information regarding the
mechanisms underlying development and progression of Wilms tumours, leading to improved treatment for
Wilms tumor patients. Both C/EBPB and CLK1 may also have roles in other human cancers.
Research achievements (from final report):
We successfully developed a lentiviral system for expressing CEBP-beta in cultured cells. One vector
expresses the full-length message, including all three protein forms of CEBP-beta, and the other expresses only
the LIP (short) isoform, which acts as a dominant negative. These vectors are available for further research
projects., We successfully developed a method for sub-kidney capsule grafts of tumour cells to produce
xenograft tumours using fluorescently labelled cells. The tumours produced by these cells could then be
followed non-invasively over time using a fluorescent in vivo imaging system developed in our Institute.
Expected future outcomes:
This research will not be continued as, although we were able to develop several techniques for culture and
xenograft propogation, we were unable to address the main hypotheses through the lack of success in tumour
propogation with the Wilms tumour cells.
Name of contact:
Bryan RG Williams
Email/Phone no. of contact:
bryan.williams@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491106
Start Year: 2008
CIA Name: Prof Bryan Williams
End Year: 2010
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Biotechnology not elsewhere classified
Total funding: $504,097
Title of research award:
Protein-RNA recognition in innate immunityProtein-RNA recognition in innate immunity
Lay Description (from application):
Protein-RNA interactions are critical in regulating the response to virus infections, and controlling the
expression of genes involved in inflammation. Small interfering RNAs (siRNAs), important tools in gene
discovery and potential therapy against virus infections and cancer, can activate the innate immune response.
By understanding protein-siRNA interactions, we will gain new insights into the design of siRNAs for studying
gene regulatory networks and for practical application in medicine.
Research achievements (from final report):
In this research project we have investigated sensing of molecules of RNA mimicking viral products by the
immune system. We have shown that the exquisite specificity of detection of RNA sequences could vary
greatly with as little as one base substitution, and changed according to the secondary structure of the RNAs
studied. Relying on these observations, we have characterised a structural motif which, in conjunction with
therapeutic RNA molecules with gene-specific targeting function, can be used to activate the immune system
and enhance antiviral/antitumoural activities. We have also demonstrated the important genetic regulation of
the innate immune sensor Toll-like receptor 8, in the functional sensing of bacterial RNA., These findings
provide new insights into the mechanisms used by the immune system to detect viral/bacterial RNAs, and how
to manipulate them for enhanced antiviral/antitumoural activities promoted by synthetic therapeutic RNAs.
These works have all been published in high impact journals (Journal of Immunology, Molecular Therapy and
Human Mutation).
Expected future outcomes:
The creation of therapeutic small interfering RNAs inducing immune activation could be used as a potent
antiviral and antitumoural strategy.
Name of contact:
Prof. Bryan Williams
Email/Phone no. of contact:
bryan.williams@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491117
Start Year: 2008
CIA Name: Prof Jamie Rossjohn
End Year: 2010
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Medical Biochemistry: Proteins and Peptides
Total funding: $521,961
Title of research award:
An X-ray crystallographic investigation into the adaptive immune response to Epstein Barr VirusAn X-ray
crystallographic investigation into the adaptive immune response to Epstein Barr Virus
Lay Description (from application):
This proposal is focussed on understanding the precise shape of proteins that control the immune response to
Epstein Barr Virus. EBV is an ubiquitous human pathogen that has been linked to a number of cancers. This
research proposal will further our understanding of the immune response to EBV, which will lay the
foundations for developing therapeutics against this disease.
Research achievements (from final report):
, Our project has gained a greater understanding of Antigen presentation and recognition in the context of the ,
protective immune response to Epstein-Barr virus (EBV). From these investigations on EBV we have begun to
, unravel the impact of MHC polymorphism and T cell repertoire selection. As EBV represents a significant
threat to , human health, understanding these parameters is important for vaccine design and immunotherapy.
Expected future outcomes:
To further our understanding of the immune response (anti-viral T cell response) to EBV and other human
pathogens.
Name of contact:
Prof. Jamie Rossjohn
Email/Phone no. of contact:
Jamie.Rossjohn@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491151
CIA Name: Prof Robert Medcalf
Admin Inst: Monash University
Main RFCD: Gene Expression
Total funding: $508,839
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Post-transcriptional regulation of plasminogen activator inhibitor 2 gene expressionPost-transcriptional
regulation of plasminogen activator inhibitor 2 gene expression
Lay Description (from application):
Plasminogen activator inhibitor type 2 (PAI-2) is a protease inhibitor that has intracellular and extracellular
functions. The PAI-2 gene is highly regulated at the level of PAI-2 mRNA stability. We have identified regions
within the PAI-2 transcript essential for this regulation and a number of novel proteins that engage these
regions. This project is aimed at understanding how these and other proteins control PAI-2 expression at the
mRNA level.
Research achievements (from final report):
The control of gene expression occurs at many levels: transcription, mRNA accumulation, protein sysnthesis
and export. This project specifically addressed the post transcriptional regulation of plasminogen activator
inhibitor 2 (PAI-2). PAI-2 is strongly implicated in cytoprotection and neuroprotection and is one of the most
regulated genes known, being increased more than 1800-fold in some cells during inflammatory conditions.
PAI-2 expression is also strongly influenced at the post transcriptional level, specifically at the control of
mRNA stability. This project was designed to understand the mechanisms by which the PAI-2 gene was
controlled at the level of mRNA stability. PAI-2 mRNA is naturally an unstable transcript and we had already
established that the 3'-UTR of the PAI-2 transcript harboured most of the information needed to implement this
instability. We also had strong evidence to implicate a specific sequence of AU-rich elements (ARE) within the
3'-UTR that were essential for this process. However, this project revealed that there are in fact 3 critical ARE
elements that appear to cooperate in this process under normal conditions in a manny very similar to that seen
in the 3'-UTR of cytokines. This finding resulted in a publication in FEBS J (2010) and a review article in
Methods in Enyzmol (2011). Since ARE-mediated mRNA decay is linked to the regulation of up to 10% of all
genes, our research will have broader implications in to the broader field of post-transcriptional regulation of
gene expression. Hence this project has redefined the mechanism by which the PAI-2 gene is regulated at the
post transcriptional level and has paved the way for further investigation.
Expected future outcomes:
We are also working towards understanding how these cooperating ARE regions in the PAI-2 3-UTR influence
the mRNA decay characteristics of this transcript during induction by inflammatory stimuli. We are also
pursuing this in neuronal systems since PAI-2 is now identified as a powerful neuroprotective protein that is
also upregulated 1800-fold in brain tissue during injury..
Name of contact:
Robert Medcalf
Email/Phone no. of contact:
robert.medcalf@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491176
Start Year: 2008
CIA Name: Prof Phillip Bird
End Year: 2010
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $816,674
Title of research award:
Regulation of leukocyte lifespan by granzyme B and PI-9Regulation of leukocyte lifespan by granzyme B and
PI-9
Lay Description (from application):
To fight infection or cancer the body produces specialized cells called cytotoxic lymphocytes (CLs) which
target and eradicate abnormal cells. The number of CLs increases dramatically during infection, and decreases
following infection. How this population decrease is controlled is not fully understood, but we propose that a
protein used by the CL to kill targets also triggers suicide of the CL after it has destroyed a certain number of
targets. How this is achieved is the focus of this project.
Research achievements (from final report):
We have examined a mechanism that potentially controls the lifespan of "killer" white cells used by the
immune system to target and kill virus-infected cells. Normally these killers work by injecting the target cell
with a pre-packaged toxic enzyme (granzyme B) which triggers it to die. When the infection is cleared and the
killer's work is done, it must die itself so it poses no danger to normal cells. We have shown that one way
killers can die occurs because an inhibitor (PI-9), which protects them from their own granzyme B, is
inactivated gradually as they work, and they cannot survive low level leakage of granzyme B into their own
interiors. Inactivation of PI-9 occurs due to damage caused by exposure to reactive oxygen species generated as
the killers are working., In the future, manipulating the GrB - PI-9 balance in specific cells may provide new
avenues for treatment. For example, there are types of cancers arising from killer cells (e.g. extranodal NK/T
cell lymphoma and anaplastic large T cell lymphoma) which resist conventional treatment: promoting
granzyme B leakage and/or inactivating PI-9 in these cells may induce them to die. Other cancer cells switch
on GrB expression: therapies that increase GrB leakage should induce such cells to die.
Expected future outcomes:
The work will contribute to a better understanding of immune system function, which is important for vaccine
development and treatment for maligancies and immune pathologies.
Name of contact:
Prof Phillip Bird
Email/Phone no. of contact:
phil.bird@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 516750
CIA Name: Prof Graham Lieschke
Admin Inst: Monash University
Main RFCD: Haematology
Total funding: $495,490
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
The Role of Med12, a subunit of RNA polymerase II mediator, in haemopoiesisThe Role of Med12, a subunit
of RNA polymerase II mediator, in haemopoiesis
Lay Description (from application):
In a screen of zebrafish for mutations in blood cell development, we isolated a mutant called syrah. The
mutation causing the blood defect was identified in a gene called med12, which encodes a component of the
RNA transcription machinery in cells. To understand how this mutation causes a reduction in blood cells, we
will identify the proteins that interact with the med12 protein. Understanding the pathway involved may lead to
the discovery of new causes of human congenital blood diseases.
Research achievements (from final report):
The project evaluated the role in blood cell development of a protein called Med12, which is a RNA
polymerase subunit important in gene transcription. A zebrafish mutatnt in which this gene is defective fials to
form white blood properly. This project studied the cell biological, molecular biological and biochemical basis
for this. These studies contribute to an increasing recognition that proteins that are needed for basic cellular
functions can exert differential effects in specific tissues, through differential regulation of the abundance,
biochemistry and interaction with critical partners.
Expected future outcomes:
As these studies were nearing completion, the work of others indicated that Med12 dysfunction was common
in uterine tumours. Our genetic and biochemical studies will remain relevant to this increasing interest in
Med12, and to future studies seeking to understand the basis of its different roles in different tissues.
Name of contact:
Graham Lieschke
Email/Phone no. of contact:
Graham.Lieschke@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 519501
CIA Name: Dr He Li
Admin Inst: Monash University
Main RFCD: Oncology and Carcinogenesis
Total funding: $430,813
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Molecular targeting to telomerase and cancer cell immortality by a novel inhibitorMolecular targeting to
telomerase and cancer cell immortality by a novel inhibitor
Lay Description (from application):
Infinite growth of cancer cells is a hallmark of cancer. Telomerase is required for cancer cell immortality.
Inhibition of telomerase may thus offer an opportunity to stop cancer cells. We have identified an inhibitor of
telomerase. This project will study the mechanisms of action of the novel inhibitor, investigating how to
control cancer cell immortality as a baseline for more applied anti-cancer therapeutic studies.
Research achievements (from final report):
Telomerase represents an important target for making new anticancer drugs. The immortality of cancer cells
requires telomerase. However, the control mechanism of telomerase, thus cancer immortality remains
unknown. This project has defined a unique peptide that inhibits telomerase in cancer cells. For the first time,
we have discovered that the telomerase inhibitory peptide interacts with telomerase RNA component directly,
providing the basis of telomerase inhibition and the site for further intervention in designing cancer cell
immortality inhibitors.
Expected future outcomes:
An anti-cancer immortality inhibitor will be developed based on the telomerase inhibitory peptide and its
action site in the telomerase TERT and TERC interface. The peptide and its remodeling derivatives would be
the candidates of telomerase inhibitors potentially for arresting the immortality of various types of cancer cells.
Name of contact:
He Li
Email/Phone no. of contact:
he.li@mcri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 519510
CIA Name: Dr Natalie Borg
Admin Inst: Monash University
Main RFCD: Tumour Immunology
Total funding: $380,559
Start Year: 2008
End Year: 2012
Grant Type: Career Development Fellowships
Title of research award:
The structural basis of T cell recognition in the context of lipid presentation and the CD1 isoformsThe
structural basis of T cell recognition in the context of lipid presentation and the CD1 isoforms
Lay Description (from application):
CD1 molecules are critical in our host-defence against microbial pathogens. They survey our body for
microbial lipids and then present them to our immune system for surveillance by T cell receptors. We aim to
understand how a T cell receptor interacts with a CD1/lipid molecule. This interaction is crucial to the
activation of our immune response and hence the elimination of the microbe. Once understood, this interaction
can potentially be modified and has immunotherapeutic potential.
Research achievements (from final report):
NKT cells are a type of white blood cell that survey lipid fragments captured from within the cell by a
molecule called CD1d. If the lipid is foreign to the body then the NKT cell generates an appropriate immune
response to protect the body. Numerous research achievements were made during this research award. The
NKT/lipid/CD1d interaction was fully described visually (atomic resolution) and functionally. The results
generated were quite unexpected and monumentally transformed the research field. The research conducted
paves the way for the design of lipids that can potentially modulate the immune response and may be effective
towards diseases such as arthritis and atherosclerosis.
Expected future outcomes:
With additional studies of a similar nature, it is expected that we will understand how the precise structure of
the lipid captured by CD1d can dictate the immune response generated by NKT cells. This body of information
will enable us to design lipids of a precise structure to modulate the immune system.
Name of contact:
Natalie Borg
Email/Phone no. of contact:
natalie.borg@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 519518
Start Year: 2008
CIA Name: A/Pr Richard Ferrero
End Year: 2010
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Medical Microbiology not elsewhere classified
Total funding: $306,511
Title of research award:
Bacterial outer membrane vesicles as immunomodulatory agents in Helicobacter pylori infectionBacterial outer
membrane vesicles as immunomodulatory agents in Helicobacter pylori infection
Lay Description (from application):
Chronic inflammation of the stomach is a hallmark of Helicobacter pylori infection, and is a precursor to peptic
ulcer disease and cancer. Like many other bacteria, H. pylori sheds spherical blebs from its surface. These
blebs bind to stomach cells in vitro and have been found in stomach biopsies of H. pylori-infected subjects. The
aims of the work are to investigate the mechanisms whereby H. pylori blebs enter and disseminate within host
cells, and how this may contribute to inflammation.
Research achievements (from final report):
We demonstrated that bacterial outer membrane vesicles (OMVs) are able to enter both non-polarised and
polarised monolayers of epithelial cells via a mechanism involving cholesterol-enriched microdomains.
Preliminary studies using endocytosis inhibitors showed that actin-dependent macropinocytosis and/or clathrindependent endocytosis are required for entry and that this requirement is dependent upon OMV size. , OMV
entry in epithelial cells was accompanied by the induction of a pro-inflammatory signalling cascade. Extensive
in vitro and in vivo experiments allowed us to definitively establish the role of the innate immune molecule,
NOD1, in the induction of this signalling. Moreover, we showed the critical role of this molecule in the
development of OMV-specific adaptive immune responses in vivo. , We next examined the antigen-presenting
functions of OMV-stimulated cells, as well as of the host cell blebs released by these cells (exosomes). OMVs
were able to up-regulate MHC class II molecule expression and apical chemokine responses in these cells and
to activate cell proliferation in human T cells ex vivo. Consistent with the latter finding, OMV antigens were
detected in the exosomes from OMV-stimulated cells. Following a proteomic analysis of H. pylori OMVs, we
identified 27 proteins, of which three were chosen for protein tagging studies. Five H. pylori strains were
engineered to each produce OMVs expressing MHC Class I- and II-specific OVA epitopes translationally
fused to one of the three OMV-associated proteins. These H. pylori strains and their OMVs are being used to
determine the mechanism of OMV antigen presentation in vitro and in vivo.
Expected future outcomes:
Elucidation of the role of bacterial OMVs in H. pylori inflammation and recognition that these bacterial
structures are likely to be important in driving the inflammation associated with bacterial infections. , The
development of bacterial OMVs for use in a variety of treatment strategies, including vaccination.
Name of contact:
A/Prof Richard L. Ferrero
Email/Phone no. of contact:
Richard.Ferrero@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 519539
CIA Name: Dr Elizabeth Williams
Admin Inst: Monash University
Main RFCD: Oncology and Carcinogenesis
Total funding: $422,781
Start Year: 2008
End Year: 2012
Grant Type: Career Development Fellowships
Title of research award:
Mechanisms of metastasis in urological cancersMechanisms of metastasis in urological cancers
Lay Description (from application):
The spread of cancer to other organs is responsible for 90% of cancer deaths. This proposal seeks to determine
how urological tumours (prostate and bladder) spread around the body. Cancer cell and animal models are an
integral component of the research, and together with data obtained in human cancer specimens provide a
comprehensive, powerful approach to identify key pathways involved in tumour spread. This is critical for the
design of new therapies to treat and-or prevent tumour spread.
Research achievements (from final report):
This research award has enabled us to determine the molecular control of lymphatic endothelial cell function
and investigate the contribution of this circulatory system to lymph node metastasis in the context of prostate
cancer. We have also demonstrated the importance of tumour cell plasticity in the development of clinically
significant metastasis.
Expected future outcomes:
We expect to identify novel modulators of tumour cell plasticity, and establish how these may be targeted to
alter disease progression and therapeutic response in advanced cancer.
Name of contact:
Elizabeth Williams
Email/Phone no. of contact:
ed.williams@qut.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 519564
CIA Name: Dr Stuart Ellem
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $291,310
Start Year: 2008
End Year: 2012
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Linking Estrogens, Prostatitis and Prostate CancerLinking Estrogens, Prostatitis and Prostate Cancer
Lay Description (from application):
Prostatitis is very common and a significant health issue that affects men from their 20's. Estrogens promote
inflammation and inflammation is associated with the development of cancer. If this study links estrogens,
prostatitis and prostate cancer, we can provide better treatment for prostatitis, thus preventing progression to
prostate cancer
Research achievements (from final report):
This work investgated the role of estrogen in prostate inflammation (prostatitis), and their subsequent
relationship to the development of prostate cancer. Prostatitis is highly prevalent but poorly understood, while
inflammation has bene linked to the development of cancer in many tissues, including in the prostate. The work
in this project has led to a number of high impact publications (inclding one in the American Journal of
Pathology) and has been the basis for several invited international symposium lectures highlighting the role of
estrogen (and mast cells) in the development of prostatitis and progression to prostate cancer. Overall, this
study has demonstrated a continuum, with increased estrogen exposure leading to the development of
prostatitis, which, in turn, leads to the development of prostate cancer. This work has also revealed a novel role
for mast cells as mediators of this process. Ultimately this may provide the basis of new therapeutics and/or
diagnostics for prostatitis and prostate cancer.
Expected future outcomes:
The role of mast cells within the prostate has previously received little attention. The data from this work,
therefore, will form the basis of future projects that are directed at understanding their contribution to the
development and/or progression of prostate diseases and their potential as a therapeutic target.
Name of contact:
Dr Stuart Ellem
Email/Phone no. of contact:
Stuart.Ellem@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 519581
CIA Name: Dr Michelle Halls
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $385,298
Start Year: 2008
End Year: 2013
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
The role of cellular microdomains in G-protein coupled receptor signalling.The role of cellular microdomains
in G-protein coupled receptor signalling.
Lay Description (from application):
Molecules communicate with cells by attaching to proteins called receptors on the outside of cells, and
triggering a series of events inside the cell. These events initially include the assembly of multiple proteins at
the cell surface. This project will examine the formation of receptors and other proteins into these
‘communication complexes’. This will provide novel targets for more selective drug development.
Research achievements (from final report):
G protein-coupled receptors are specialised proteins on the surface of cells. They are the targets of 30% of
currently available pharmaceuticals that treat a variety of human diseases. One of these proteins is a target for
the hormone relaxin, which plays an important role in implantation during pregnancy, and is currently in
clinical trials for use as a therapy during heart failure. While we have known of the existance of this hormone
since 1928, there has long been a paradox - the amount of relaxin that is typically found in the circulation does
not have any effect on cells., This Fellowship allowed me to persue my research at the University of
Cambridge, where I learnt cutting-edge techniques that allow sensitive detecion of small responses inside
discrete areas of single live cells. By using this technology, I was able to discover that cells do respond to the
low amounts of relaxin present in the circulation. In fact, this approach revealed some very unique and exciting
properties of G protein-coupled receptors that only occur following their assembly into specialised networks in
cells., Since my return to Australia and Monash University, I have continued this groundbreaking research into
the unique properties of G protein-coupled receptors following their specific organisation into these specialised
cellular networks. Furthermore, I have established and begun to develop further, the cutting-edge technology
that I learnt at the University of Cambridge, at the Monash Institute of Pharmaceutical Sciences.
Expected future outcomes:
The discovery of these specialised networks in cells is likely to have a significant impact on the drug discovery
field, as 30% of currently available pharmacueticals target G protein-coupled receptors. Moreover, the
development of technology brought back to Australia is likely to be of significant impact to drug discovery
research.
Name of contact:
Michelle L Halls
Email/Phone no. of contact:
michelle.halls@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 543141
CIA Name: Prof Steve Gerondakis
Admin Inst: Monash University
Main RFCD: Cellular Immunology
Total funding: $492,991
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The transcription factors c-Rel and RelA serve distinct roles in the devlopment and function of CD4 Regulatory
T cellsThe transcription factors c-Rel and RelA serve distinct roles in the devlopment and function of CD4
Regulatory T cells
Lay Description (from application):
An unfortunate consequence of immune function is that occasionally rogue immune cells are produced that
attack the host and lead to the development of so-called autoimmune diseases such as arthritis. Normally a
white blood cell called a regulatory T cell suppresses these self reactive immune cells. We have identified
factors that govern genetic programs in regulatory T cells. Understanding how these factors work should permit
the development of new strategies to combat autoimmune diseases.
Research achievements (from final report):
CD4 regulatory T cells that express Foxp3 (Tregs) play a critical role controlling normal immune responses as
well as preventing the development of autoimmune disease. Accordingly, understanding how the development
and function of this T cell lineage is regulated is an important goal of biomedical research. Research funded by
this grant established that the c-Rel transcription factor plays an essential role in promoting the development of
Tregs in the thymus, but it has a lesser role in the function of these cells once thymic development is complete.
The role of c-Rel in thymic Treg development was found to be one that involved the commitment of CD4 T
cells to the Treg lineage. This finding that c-Rel is a key regulator of Treg development could potentially offer
therapeutic avenues for manipulating Treg numbers in order to regulate the impact this lineage has in various
pathological conditions such as autoimmune disease and cancer.
Expected future outcomes:
This work has provided a foundation for determining how c-Rel controls the pattern of gene expression
responsible for Treg development and which specific c-Rel regulated genes contribute to the formation and
function of this T cell lineage.
Name of contact:
Steve Gerondakis
Email/Phone no. of contact:
steven.gerondakis@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 544302
CIA Name: A/Pr David Curtis
Admin Inst: Monash University
Main RFCD: Haematology
Total funding: $595,353
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The function of bHLH factors in adult haemopoiseisThe function of bHLH factors in adult haemopoiseis
Lay Description (from application):
Understanding how genes control the behaviour of bone marrow stem cells is currently needed for improving
recovery after chemotherapy or bone marrow transplantation and in the future, will aid the application of new
stem cell-based therapies for human diseases such as leukaemia. This research will examine how 2 closely
related genes control bone marrow stem cell growth and the decision between beocoming a red cell or a white
cell.
Research achievements (from final report):
This research demonstrated the presence of 2 proteins that work together to maintain normal numbers and
activity of blood stem cells. Too much of either protein leads to blood cancer (leukemia) whilst too little leads
to failure of blood production (aplastic anemia).
Expected future outcomes:
Finding ways to alter the expression or function of these proteins may be useful for the treatment of leukemia
and aplastic aneamia as well as expanding normal stem cells for bone marrow transplant.
Name of contact:
David Curtis
Email/Phone no. of contact:
david.curtis@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 544304
CIA Name: Prof Stephen Jane
Admin Inst: Monash University
Main RFCD: Dermatology
Total funding: $579,138
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Defects in epidermal morphogenesis in Grainyhead-like gene deficient miceDefects in epidermal
morphogenesis in Grainyhead-like gene deficient mice
Lay Description (from application):
The cells of the skin play an essential role in the development of the mammalian embryo. They are critical for
forming a protective barrier against infection and external toxins, for preventing excess fluid loss, for repair of
defects and wounds , and for the generation of hair. Our laboratory has identified a family of genes that are
critical for these processes. The aim of this study is to determine the relationship between these genes to further
our understanding of the skin and its functions
Research achievements (from final report):
This project examined the role of the Grainy head-like factors in epidermal morphogenesis. We made,
excellent progress in understanding the role of Grhl3 in both embryonic epidermal development and in, adult
epidermal homeostasis. We also made inroads in deciphering interactions between the family, members in
epidermal development.
Expected future outcomes:
These studies pave the way for further developments in understanding and management of disease processes
that involve defective epidermal migration such as failed wound repair and neural tube defects.
Name of contact:
Stephen Jane
Email/Phone no. of contact:
stephen.jane@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 545917
CIA Name: Prof Katherine Loveland
Admin Inst: Monash University
Main RFCD: Reproduction
Total funding: $511,295
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Activin in Testicular Development and DiseaseActivin in Testicular Development and Disease
Lay Description (from application):
A man's reproductive health and fertility is affected by processes that occur long before adulthood. The testis
and sperm precursor cells first form in the fetus and then grow until the time of puberty, when the upper limit
for sperm production is set. This project studies how one key signaling molecule, activin, helps establish
normal testicular architecture and drives maturation of sperm precursor cells, and how it contributes to aberrent
function in men with testicular cancer.
Research achievements (from final report):
The growth factor, activin A, was shown to play a critical role in determining how the testis grows to enable
production of adequate numbers of sperm in adult life. We discovered that activin works in the fetus to create
the correct balance between the number of cells that will form spermatozoa and the cells that form the niche in
which sperm precursors are maintained and mature. We identified a potential link between disturbances in
activin actions in the fetal and juvenile testes with events that lead to testicular cancer, the most common
cancer in young men.
Expected future outcomes:
Activin is now under intense scrutiny internationally, as a possible factor that may explain the many cases of
male infertility which are currently unexplained. We will use our discoveries to define the key steps in testis
growth that are required for normal fertility and adult health in men, and these will be applied to diagnose and
treat testicular pathologies.
Name of contact:
Kate Loveland
Email/Phone no. of contact:
kate.loveland@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 545931
CIA Name: Prof Gail Risbridger
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $594,722
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Characterising the beneficial effects of estrogen on the prostate glandCharacterising the beneficial effects of
estrogen on the prostate gland
Lay Description (from application):
Prostate cancer is hormonally regulated and currently managed by androgen ablation. This application seeks to
study the potential benefits of estrogen action for the treatment of prostate disease, including PCa. We will
show estrogen hormone action causes prostatic cell death, targeting the stem-progenitor cells so the treated
prostatic tissue does not regenerate. This project will provide pre-clinical proof of the efficacy of estrogenic
compounds as a potential therapy for prostate disease.
Research achievements (from final report):
This work investigated the biological action of a novel estrogen receptor beta (ERβ) agonist; 8β-VE2. This
compound selectively activates ERβ over ERα and does not interfere with androgen signalling. We have
produced a significant high impact publications (including PNAS) and presented several international
symposium lectures highlighting the therapeutic potential of thes ERβ agonist, based on its ability to
selectively target prostatic stem cells. , Whilst androgen deprivation therapy is standard of care for advanced
prostate cancer, it fails to target residual castrate-resistant cells that give rise to prostate cancer. Our data using
mouse and human tissues indicate that ERβ activation blocks stem cell activity in the prostate, particularly
those that are resistant to androgen deprivation therapy. This new information confirms the beneficial action of
ER activation to treat prostate disease.
Expected future outcomes:
Future studies should work towards determining the most appropriate stage of disease for these agents to be
used in the clinic. Possible strategies could include ERβ treatment in conjuction with or subsequent to androgen
deprivation therapy.
Name of contact:
Gail P. Risbridger
Email/Phone no. of contact:
gail.risbridger@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 545943
CIA Name: A/Pr Philip Thompson
Admin Inst: Monash University
Main RFCD: Enzymes
Total funding: $518,990
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Dissecting Isoform Selectivity of PI3 Kinase Inhibitors. Uncovering leads for rational drug design.Dissecting
Isoform Selectivity of PI3 Kinase Inhibitors. Uncovering leads for rational drug design.
Lay Description (from application):
The PI3 kinase enzyme controls many functions in cells and in many cases contributes to the onset and
progression of diseases such as cancer, thrombosis and inflammatory diseases. Compounds that block PI3
kinase activity may be useful drugs but will need to act specifically to minimize side effects. We aim to
understand the way in which inhibitors block the PI3 kinase activity with the belief that this information will
allow us to make better drugs.
Research achievements (from final report):
In this project, we set out with a goal to determine the mechanisms by which small molecules inhibit the class I
isoforms of PI3K which at that time was not understood. We planned to test the contribution of non-conserved
elements of the PI3K catalytic site to the observed selectivities of ligands using an experimental approach that
incorporated computer modelling, site directed mutagenesis and assays of enzyme inhibition by a range of PI3
kinase inhibitors from our compound collections. By doing so, we aimed to make accurate predictions of the
selectivity of compounds. The outcome was access to a rational drug design strategy that can significantly
expedite the development of drug candidates. Our key hypothesis that specific non-conserved regions impart
isoform selectivity on PI3K inhibitors has been confirmed. We discovered the quite distinct and varied ways
that both selective PI3K? inhibitors and PI3K? inhibitors select for their preferred target. In some cases this
means specific interactions between the inhibitor and the non-conserved residue. In other cases, the difference
results in binding pockets that are only accessable to certain isoforms. We also showed that some established
inhibitors have distinct binding kinetics, which may provide a valuable feature to target in second generation
drugs. Finally we have shown that this collected information can lead drug design by developing our own
propietary class of PI3K? inhibitors, which are under pre-clinical evaluation.
Expected future outcomes:
As highlighted above, we have developed a series of compounds that can select for one or more isoform
combinations, including the most selective inhibitors of PI3K? yet reported. These compounds are being used
in pre-clinical studies in models of cancer and thrombosis with the ultimate aim of developing a drug to treat
these conditions.
Name of contact:
A/P Philip Thompson
Email/Phone no. of contact:
Philip.Thompson@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 545983
Start Year: 2009
CIA Name: Dr Terry Kwok-Schuelein
End Year: 2012
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $290,697
Title of research award:
Roles of integrin receptors and the Helicobacter pylori protein CagL in gastritis and gastric cancerRoles of
integrin receptors and the Helicobacter pylori protein CagL in gastritis and gastric cancer
Lay Description (from application):
How the bacterium Helicobacter pylori (Hp) causes gastritis and gastric cancer in the stomach is not well
understood. Here we investigate the molecular languages used by Hp to deregulate the normal functions of the
human stomach cells. The research outcomes will on one hand help us to better understand how Hp causes
diseases, and on the other hand, facilitate the development of new antibiotics or treatment therapies to combat
gastric cancers and gastritis.
Research achievements (from final report):
Helicobacter pylori is a bacterium that infects approximately half of the world population, causing peptic ulcer
and gastric cancer in susceptible individuals. It possesses a complex transport machinery, known as the type IV
secretion system (T4SS), which delivers virulence factors into infected stomach cells. The H. pylori T4SS
stimulates massive inflammatory responses and is therefore a major virulence factor. This study revealed how
one of the T4SS components, CagL, directly drives proinflammatory responses via increasing the secretion of
the potent chemokine, interleukin-8 (IL-8). Chemokines are molecules that attract immune cells to the site of
infection to mount immune responses. Our study showed that CagL stimulates the secretion of these
'messenger' molecules by activating a receptor protein on the surface of human stomach lining cells. Changing
the regions in CagL that are important for binding to its receptor, integrin, disarmed the proinflammatory
capability of CagL. Likewise, blocking the integrin receptor on the stomach cell surface with an inhibitory
antibody had a similar anti-inflammatory effect. Using additional inhibitors, we were able to also unravel the
intracellular molecular events involved from the step of receptor activation to the ultimate production of the
chemokine IL-8. These findings provide a deeper understanding into how H. pylori hyper-stimulates
proinflammatory responses at the molecular level. Importantly, our results also suggest that certain wellcharacterised inhibitors can effectively suppress the inflammatory responses elicited during H. pylori infection,
paving ways for the development of novel anti-inflammatory therapeutic strategies for treating H. pyloriinduced gastritis and gastric cancer, and possibly also other chronic inflammatory disorders.
Expected future outcomes:
Our study suggests that well-characterised pharmaceutical inhibitors could be used to effectively suppress the
excessive inflammatory responses elicited during H. pylori infection. This paves way for the development of
novel anti-inflammatory therapeutic strategies for treating H. pylori-induced gastritis and gastric cancer, and
possibly also other chronic inflammatory disorders.
Name of contact:
Dr. Terry Kwok-Schuelein
Email/Phone no. of contact:
terry.kwok@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 545989
CIA Name: Prof Christina Mitchell
Admin Inst: Monash University
Main RFCD: Membrane Biology
Total funding: $602,673
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
MTMR4, a regulator of PtdIns(3)PMTMR4, a regulator of PtdIns(3)P
Lay Description (from application):
Normally cells only divide when they receive a stimulus from a hormone or growth factor. The PI3-kinase
pathway responds to these stimuli and has been implicated in cellular immunity as well as cancer which occurs
when cells divide uncontrollably and invade surrounding tissues. We have identified a putative oncogene
(cancer causing gene) called MTMR4 that appears to regulate cell growth/invasion and pathogen invasion of
immune cells. We aim to characterise the role of MTMR4 in these systems.
Research achievements (from final report):
Our work has established the role of the enzyme, myotubularin myopathy related protein 4 (MTMR4) in
directing biological functions within cells. This enzyme acts to turn off signals from the phosphoinositide,
PtdIns(3)P, which is present on internal cell compartments called endosomes. PtdIns(3)P directs endosome
traffic, and thereby controls the sorting of nutrient factors such as the iron carrying transferrin receptor and the
degradation of growth factor receptors. The mechanism of the formation of PtdIns(3)P is known, and it is also
appreciated that endosomal PtdIns(3)P must be removed in a coordinated fashion for normal cell function,
however the mechanism for its removal is not well understood. We have shown that MTMR4 is localized in
mammalian cells to endosomes which regulate the sorting and recycling of cargo, and that in the absence of
MTMR4, an excessive number of endosomes carry PtdIns(3)P signals. In cells which have too much MTMR4,
there is less PtdIns(3)P and a block in the sorting of transferrin through the endosome network, which is then
unable to be recycled back to the surface of the cell. Normal regulation of the sorting and recycling endosomal
network is important in many areas of cellular biology. As a regulator of PtdIns(3)P levels of this endosomal
network, MTMR4 therefore represents a potential checkpoint of control for a number processes, including
growth, development, cancer and inflammation.
Expected future outcomes:
We are utilising the models developed in our laboratory to examine in detail how MTMR4 acts to regulate
cancer progression and immune cell function to evaluate the molecular pathogenesis of these processes and to
offer novel therapeutic approaches in the future.
Name of contact:
Christina Mitchell
Email/Phone no. of contact:
Christina.mitchell@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 546016
CIA Name: Prof Leon Bach
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $550,725
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Pathways involved in the insulin-like growth factor (IGF)-independent actions of IGF binding protein6Pathways involved in the insulin-like growth factor (IGF)-independent actions of IGF binding protein-6
Lay Description (from application):
Insulin-like growth factors (IGFs) are important proteins that regulate growth. When not regulated properly,
diseases such as cancer can occur. A family of IGF binding proteins regulates IGFs. IGFBPs may inhibit IGFs
and we have shown that one of them, IGFBP-6, decreases growth of some experimental cancers. As well as
regulating IGFs, some IGFBPs alter cell behaviour independently of IGFs, and we found that IGFBP-6
stimulates cell movement in this way. We will now determine how this happens.
Research achievements (from final report):
Insulin-like growth factors (IGFs) are important proteins that regulate growth. When not regulated properly,
diseases such as cancer can occur. A family of IGF binding proteins regulates IGFs. IGFBPs may inhibit IGFs
and we have shown that one of them, IGFBP-6, decreases growth of some experimental cancers. As well as
regulating IGFs, some IGFBPs alter cell behaviour independently of IGFs, and we found that IGFBP-6
stimulates cell movement in this way. We have determined a number of key pathways involved in this action.
We have also shown that IGFBP-6 stops blood vessel growth, which is required for cancers to grow.
Expected future outcomes:
These findings indicate that IGFBP-6 has a number of actions that may decrease cancer growth, namely
inhibiting IGFs and stopping blood vessel growth. Further understanding of how IGFBP-6 increases cell
movement may allow the engineering of a protein that has enhanced anti-cancer properties.
Name of contact:
Prof Leon Bach
Email/Phone no. of contact:
leon.bach@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 546098
CIA Name: Prof David Watkins
Admin Inst: Monash University
Main RFCD: Oncology and Carcinogenesis
Total funding: $295,984
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Interactions Between Hedgehog and Ras Signaling in Lung AdenocarcinomaInteractions Between Hedgehog
and Ras Signaling in Lung Adenocarcinoma
Lay Description (from application):
Lung cancer is a common and lethal disease in our community. In this project, we explore how signaling
pathways that regulate the development of the lung in embryos contribute to the initation and progression of
lung cancer. To do this, we use a mouse model of lung cancer in which we can activate embryonic signaling
pathways in adult mice to study there effect on the disease. Understanding these pathways will help us to better
treat and prevent lung cancer in humans.
Research achievements (from final report):
Lung cancer is the commonest cause of cancer death in Australia. Since normal stem cells have the capacity to
repair injured tissues, some cancer researchers have begun to ask whether signalling pathways that regulate this
process might also be important for the initiation of lung cancer. Signaling pathways that maintain normal stem
cells are quite different from those that drive growth. Many of these pathways were first identified in fruit flies.
One of these pathways, known as "Hedgehog" has been identified as very important in normal stem cells, and
in some cancers. Our research has shown that a compound derived from a plant, known as "cyclopamine", was
able to block tumour growth by inhibiting the Hedgehog pathway. Using genetically modified mice in which
we could activate or block Hedgehog signaling in the lung, we were able to demonstrate that this pathway acts
through two distinct mechanisms, depending on the type of lung cancer.
Expected future outcomes:
This important research will help determine how to best use the new generation of Hedgehog inhibitors for
treatment of lung cancer.
Name of contact:
Neil Watkins
Email/Phone no. of contact:
neil.watkins@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 546204
CIA Name: Prof David Watkins
Admin Inst: Monash University
Main RFCD: Oncology and Carcinogenesis
Total funding: $363,828
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
An in-vivo model of acquired chemoresistance in small cell lung cancerAn in-vivo model of acquired
chemoresistance in small cell lung cancer
Lay Description (from application):
Lung cancer is a common and lethal disease in our community. In this project, we explore how a very
aggressive form of lung cancer becomes resistant to chemotherapy. To do this, we use a new mouse model of
lung cancer in which we can study how human lung cancer cells develop resistance to chemotherapy in vivo.
Understanding these pathways will help us to better treat lung cancer with chemotherapy.
Research achievements (from final report):
Lung cancer is the commonest cause of cancer death in Australia. About 15-20% of cases are "small cell" lung
cancer (SCLC), a very aggressive form of the disease. SCLC is usually very sensitive to chemotherapy, but is
very rarely cured because the tumour grows back. Since normal stem cells have the capacity to repair injured
tissues, some cancer researchers have begun to ask whether signalling pathways that regulate this process
might also be important for the initiation of lung cancer. Signaling pathways that maintain normal stem cells
are quite different from those that drive growth. Many of these pathways were first identified in fruit flies. One
of these pathways, known as "Hedgehog" has been identified as very important in normal stem cells, and in
some cancers. Our research has shown that a compound derived from a plant, known as "cyclopamine", was
able to block tumour growth by inhibiting the Hedgehog pathway. Unlike conventional cancer therapies,
Hedgehog inhibitors are not effective in most established tumors. Instead, they seem to work by blocking the
ability of cancers to regenerate from a small residual number of cells. Using SCLC cells taken directly from
patients and grown in mice, we were able to demonstrate that Hh inhibitors block the regeneration of cancer
cells following chemotherapy. This important research will help determine how to best use the new generation
of Hedgehog inhibitors for treatment of lung cancer.
Expected future outcomes:
This important research will help determine how to best use the new generation of Hedgehog inhibitors for
treatment of lung cancer.
Name of contact:
Neil Watkins
Email/Phone no. of contact:
neil.watkins@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 575502
Start Year: 2009
CIA Name: Prof Raymond Norton
End Year: 2013
Admin Inst: Monash University
Grant Type: NHMRC Research Fellowships
Main RFCD: Medical Biochemistry: Proteins and Peptides
Total funding: $733,897
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a structural biologist investigating the structure and function of malaria surface proteins as vaccine
candidates, regulators of cytokine signalling and pharmacologically active toxins.
Research achievements (from final report):
My research program focused on developing new therapeutics targeting diseases such as bacterial infections,
malaria, autoimmune diseases (in particular multiple sclerosis) and chronic pain. This has been achieved by
combining my expertise in structural biology and structure-based design with two new approaches: 1)
Fragment-based drug design, and 2) Development of peptides as therapeutics., A peptide analogue to which my
research contributed extensively entered Phase I clinical trials for the treatment of autoimmune diseases such as
multiple sclerosis in late 2012 and is progressing to Phase II clinical trials later in 2014.
Expected future outcomes:
My fellowship was renewed commencing in January 2014, allowing me to continue to progress a range of
projects toward these goals. We are developing anti-infective and anti-malarial drugs, drugs for the treatment
of autoimmune diseases, and novel vaccines targetting malaria.
Name of contact:
Ray Norton
Email/Phone no. of contact:
ray.norton@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 596849
CIA Name: Dr Georg Ramm
Admin Inst: Monash University
Main RFCD: Signal Transduction
Total funding: $299,432
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Molecular Regulation of the Serine-Threonine Kinase ULK1 in AutophagyMolecular Regulation of the SerineThreonine Kinase ULK1 in Autophagy
Lay Description (from application):
Autophagy or self eating is a basic cellular process and can have either beneficial or adverse effects in cancer.
It is essential to determine the status of autophagy in patients before considering drugs that block autophagy for
therapy. A protein called ULK1 is needed for autophagy and may emerge as a pathological marker for
autophagy in cancer as well as a potential drug target. This grant proposal will study ULK1 regulation and will
lay the scientific foundation for its medical application.
Research achievements (from final report):
Autophagy, literately meaning 'self eating', is a fundamental cellular process that allows organisms to survive
nutrient deprivation and stress. This happens via the degradation and recycling of cellular components that are
either damaged through stress or are less important for survival during starvation. The medical relevance of this
evolutionary conserved mechanism has only recently come into the spotlight with research showing roles in
cancer, infectious diseases, neurodegeneration, myopathies, aging, and liver disease. In cancer, autophagy on
the one hand keeps cells healthy and prevents tumorigenesis, but on the other hand assists cancer cells to cope
with starvation stress in a poorly vascularised tumour. The goal of our research was to uncover how cellular
energy levels control autophagy. Before the start of our research the model was that the sensing of cellular
energy levels was coupled to autophagy exclusively via mTOR, a central regulatory node in cellular energy
metabolism. Our results have fundamentally changed the understanding of this pathway. We showed that a
major sensor of cellular energy level, the protein kinase AMPK, is directly linked to the autophagy regulator
ULK1. In addition, we show that insulin, a hormone signalling the availability of glucose, directly regulates
autophagy without the involvement of mTOR. The research has uncovered molecular mechanisms of
autophagy regulation providing the molecular tools to study the regulation of autophagy in disease.
Expected future outcomes:
The molecular tools developed could become potential diagnostic markers for autophagy induction in disease.
In addition, the identification of markers for key regulatory steps in autophagy will facilitate the screening for
molecular inhibitors of autophagy.
Name of contact:
Dr Georg Ramm
Email/Phone no. of contact:
georg.ramm@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 603130
CIA Name: Prof Edouard Nice
Admin Inst: Monash University
Main RFCD: Cancer Diagnosis
Total funding: $562,399
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Quantitative proteomic analysis of faecal biomarkers for colon cancerQuantitative proteomic analysis of faecal
biomarkers for colon cancer
Lay Description (from application):
We have identified a number of potential biomarkers present in the stools of patients with colorectal cancer
(CRC). We will use quantitative mass spectrometric techniques that we have developed to validate these
biomarkers on a large number of faecal samples from patients with CRC and multiple control groups. We
believe these studies will lead to a new panel of biomarkers which will improve the detection of early forms of
colon cancer, thus reducing death from this disease.
Research achievements (from final report):
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women worldwide. If
detected early before the disease has spread to other organs, more than 90% of the patients can be effectively
cured by simple surgical resection. Early detection is therefore paramount. We have shown that stool samples
from patients with asymptomatic advanced adenomas or CRC contain signature proteins and/or peptides
relating to the presence of the adenoma or tumour that are relatively more abundant in faeces than in blood,
thereby facilitating their detection. These proteins may be released by secretion, leakage or exfoliation and may
refelect different aspects of the cancer biology (e.g, altered signaling pathways, inflammation, bleeding). Using
faecal samples from patients with colorectal cancer, benign bowel disease and volunteers who have no
indication of any cancerous lesions at colonoscopy, we have used multidimensional micropurification
techniques coupled with mass spectrometry to generate a comprehensive database that catalogues, for the first
time, the faecal proteome. This database contains more than 550 proteins and 3500 proteotypic peptides that
have then been used to develop sensitive and specific quantitative multiplexed assays using a mass
spectrometric technique known as multiple reaction monitoring. Assays have been developed whereby more
than 70 potential biomarkers can be interrogated in a single analysis using unfractionated faecal extracts. This
has allowed the development of a novel panel of biomarkers that appears to have better selectivity and
sensitivity that the current faecal occult blood test that is the current primary screen for CRC.
Expected future outcomes:
It is anticipated an improved diagnostic test for CRC can be developed and fully validated. This would reduce
the number of unnnecessary colonoscopies currently performed due to false positive FOBT results.
Name of contact:
Prof. Edouard Nice
Email/Phone no. of contact:
ed.nice@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606402
CIA Name: Prof Christina Mitchell
Admin Inst: Monash University
Main RFCD: Signal Transduction
Total funding: $689,474
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Role of the 72kDa 5-phosphatase in human diseasesRole of the 72kDa 5-phosphatase in human diseases
Lay Description (from application):
We have identified a novel gene, Inpp5e, that when mutated causes a disease similar to Joubert syndrome and
MORMS disease which leads to abnormal movements, developmental delays, mental retardation, abnormal
breathing and eye movement. We have identified a candidate gene for these diseases and have shown that
deletion of this gene in mice results in similar pathology. We aim to determine the mechanism by which Inpp5e
regulates human development and disease.
Research achievements (from final report):
We characterised the function of a human gene, Inpp5e, in mice and cultured cells. The INPP5E gene is
mutated in human ciliopathy syndromes, which are disorders characterised by developmental abnormalities
affecting organs including the brain and kidneys. There are currently no cures or successful treatments for
ciliopathy syndromes. How mutation of INPP5E causes developmental abnormalities is unknown and formed
the focus of this research. We generated mice harbouring deletion of the Inpp5e gene and observed
abnormalities which recapitulated the human ciliopathy syndromes. These mice provided valuable tools for
studying the basis of disease in INPP5E mutated ciliopathies. We conducted studies in cells to uncover how
Inpp5e regulated signalling pathways which contribute to human diseases such as polycystic kidneys.
Collectively, these studies revealed novel and signifcant roles for INPP5E, and this research may reveal future
therapeutic strategies for ciliopathies.
Expected future outcomes:
We have generated mice harbouring Inpp5e deletion to understand the basis of disease evident in various
organs arising from Inpp5e mutation/deletion. In ongoing studies, we will uncover the molecular pathways
coordiated by Inpp5e in these tissues and endeavour to define novel therapeutic targets/strategies for ciliopathy
treatment.
Name of contact:
Prof. Christina Mitchell
Email/Phone no. of contact:
christina.mitchell@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606404
CIA Name: A/Pr Gregory Hannigan
Admin Inst: Monash University
Main RFCD: Cancer Cell Biology
Total funding: $452,249
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The role of ILK in Hedgehog signaling and medulloblastoma.The role of ILK in Hedgehog signaling and
medulloblastoma.
Lay Description (from application):
Molecular signaling pathways regulate normal embryo development, and deregulated signaling by these
pathways causes many cancers. Hedgehog (Hh) is a signalling pathway commonly activated by mutations in
specific genes to cause cancer, including medulloblastoma, the most common brain tumour of childhood. We
have discovered novel protein interactions in the Hh pathway, and will use animal models of Hh-dependent
medulloblastoma to investigate new anti-cancer drugs targetting these proteins.
Research achievements (from final report):
This work identifies a novel and unexpected interaction of a protein kinase, ILK, with the Hedgehog (HH)
developmental signalling pathway, which when dysregulated causes a number of common cancers. We have
shown that ILK localizes in a small but critically important structure at the cell surface called the primary
cilium. This structure is required for HH signalling and regulation of cell growth, and we now find that
inhibiting ILK activity using genetic or pharmacologic approaches suppresses Hedgehog signalling. Aberrant
HH signalling is increasingly understood to cause a number of human malignancies, including breast, prostate
and pancreatic cancers. We have developed a rigorous mouse genetic model to study the role of ILK in a HHdriven brain tumour called medulloblastoma (MB), which affects a hindbrain structure called the cerebellum.
We have selectively deleted the ilk gene from HH-activated cerebellar neuronal cells that initiate MB, and
observe dramatic improvement in tumour-free survival compared to mice with the intact ilk gene. Strikingly,
we have observed no MB tumours in the ilk-deleted mice, compared to 15-20% tumour incidence in mice with
intact cerebellar ilk. Cell biology experiments suggest mechanisms underlying this ilk effect on MB. Using
state-of-the art imaging and protein-protein interaction protocols we have documented physical interaction of
ILK with Smo, the HH pathway effector that is required for MB. Importantly, this interaction occurs in the
primary cilium, which is also required for MB development. This work identifies ILK as a promising target for
development of drugs against HH-driven cancers.
Expected future outcomes:
We expect that as a result of our work ILK will emerge as a promising target for development of therapeutics
against cancers exhibiting aberrant activation of cilia-dependent HH signalling.
Name of contact:
Greg Hannigan
Email/Phone no. of contact:
greg.hannigan@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606492
CIA Name: Prof Gail Risbridger
Admin Inst: Monash University
Main RFCD: Cancer Cell Biology
Total funding: $559,636
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Defining Stromal-Cancer Cell Interactions for Xenografting Human Prostate CancerDefining Stromal-Cancer
Cell Interactions for Xenografting Human Prostate Cancer
Lay Description (from application):
Prostate Cancer research continues to be hindered by a lack of laboratory models to understand disease
progression and design new drugs to cure the disease. In this study, we propose to use a new and reliable
method of growing human prostate cancer tissue in mice. Using this model, we will investigate the role of
hormone signalling and cellular communication in prostate cancer that may lead to new therapies for men
diagnosed with organ-confined disease.
Research achievements (from final report):
Primary scientific findings from this project described the establishment of a new model to examine the growth
and progression of human prostate cancer, specifically from men with early stage, localised, disease. Prostate
cancer specimens can now be manipulated and tested in the laboratory, facilitating major advances in studying
the genetics and molecular biology of prostate cancer, which were not possible in previous xenograft models
which had low survival and growth rates. We can now truly test for the existence of prostate cancer
repopulating cells and advance our fundamental understanding of the hierarchical organisation of prostate
tumors.We have used this methodology to identify and study castrate-tolerant prostate cancer cells that are
present in early stage disease, that haven't yet been subjected to androgen withdrawal therapy. The discovery of
these cells will greatly improve our ability to increase the effectiveness of current anti-androgen therapies, and
understand the cellular changes that occur as advanced diseae ensues.
Expected future outcomes:
The new xenografting techniqe developed by this project will allow discovery of new prostate cancer
therapeutics and provide a model system for pre-clinical evaulation on human tissues.
Name of contact:
Prof. Gail P Risbridger
Email/Phone no. of contact:
gail.risbridger@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606503
CIA Name: Dr Duangporn Jamsai
Admin Inst: Monash University
Main RFCD: Reproduction
Total funding: $506,426
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The mechanism of spermatid differentiation - A link to tumour suppressionThe mechanism of spermatid
differentiation - A link to tumour suppression
Lay Description (from application):
To discover novel regulators of male fertility, we have screened libraries of mutant mice generated by a
chemical mutagen. This project aims to define the function of the mutated gene identified in a male-specific
infertile mutant mouse line. The mutated gene has been proposed to play a role in regulating cell death and
suppress lung tumour formation. Our data may reveal novel options for male infertility treatment and for the
development of male contraception and lung cancer biomarkers.
Research achievements (from final report):
This project revealed the function of a previously uncharacterised gene, Rbm5, in the aetiology of two diseases
of major national and international significance, male infertility and lung cancer. Our data provided great
insights into mechanisms involved in sperm production and most importantly the aetiology of infertility, which
affects one in 25 Australian men. Furthermore, we have discovered that RBM5 is a critical regulator of lung
cancer initiation and progression. These findings open up an exciting avenue for future studies on the
development of diagnostic/therapeutic biomarkers for lung cancer.
Expected future outcomes:
Our data revealed several potential targets for the development of diagnostic/therapeutic markers for male
infertility and lung cancer.
Name of contact:
Dr. Duangporn Jamsai
Email/Phone no. of contact:
duangporn.jamsai.monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606557
Start Year: 2010
CIA Name: Prof James Whisstock
End Year: 2013
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $876,679
Title of research award:
Structural, Biochemical and Biophysical Studies on PerforinStructural, Biochemical and Biophysical Studies
on Perforin
Lay Description (from application):
This proposal focuses upon understanding the structure and mechanism of perforin, a protein that performs a
crucial role in human immunity. We will investigate how certain mutations in perforin cause deficiency and
disease. Our work will also seek to understand how potential therapeutics act to modulate perforin function.
Finally, through a combination of biochemical and structural studies we will elucidate the details of perforin
mechanism.
Research achievements (from final report):
All aspects of this grant were successfully achieved. A major achievement of this project was determining the
structure of perforin as well as the the low resolution structure of the perforin pore. This work was published in
Nature (Law et al., 2010, Nature) and has contributed to a seeding drug discovery program funded by the
Wellcome Trust (CIs Trapani, Hill, Denny and Whisstock). Perforin inhibitors are anticipated to be of
therapeutic utility in improving the success of bone marrow transplantation (a therapy used to treat a range of
haematological malignacies).
Expected future outcomes:
The development of perforin inhibitors of utility in treating a range of different immune driven diseases, as
well as in improving the success of bone marrow transplantation.
Name of contact:
James Whisstock
Email/Phone no. of contact:
James.Whisstock@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606562
CIA Name: Prof Moira O'Bryan
Admin Inst: Monash University
Main RFCD: Reproduction
Total funding: $474,310
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Cysteine-rich secretory protein regulation of ion channels in male fertility and prostate cancerCysteine-rich
secretory protein regulation of ion channels in male fertility and prostate cancer
Lay Description (from application):
Diagnosis of the precise causes of male infertility and the development of male contraceptives requires
improved understanding of sperm function. The Cysteine-Rich Secretory Proteins (CRISPs) are produced in
the male reproductive tract where they regulate sperm function. Our project will demonstrate the essential
requirement for CRISPs in sperm function and investigate their role in other tissues of the reproductive tract,
including the prostate where they may be involved in prostate cancer.
Research achievements (from final report):
We have identified CRISP4 as a regulator of sperm function. Specifically we have shown that via it's
interaction with another protein, TRPM8, CRISP4 contributes to the regulation of the sperm's ability to fertilize
ie. undergo the acrosome reaction. Our data provides evidence that CRISPs are regulators of ion channels and
as such they may have utility in the treatment of several diseases wherein ion channels are implicated. In
addition we have developed a greatly improved method to produce CRISPs, and have preliminary to suggest
that CRISP3 has a role in prostate cancer progression.
Expected future outcomes:
We anticipate at least two additional publications from this project (the data is being finalized by a PhD
student). This is only the second time wherein the function of a mammalian CRISP has been defined. We
anticipate our data may contribute to the development of ion channel-mediated therapies. We are currently
following up on the role of CRISP3 in prostate cancer.
Name of contact:
Moira O'bryan
Email/Phone no. of contact:
moira.obryan@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606605
CIA Name: Prof Tony Tiganis
Admin Inst: Monash University
Main RFCD: Cancer Cell Biology
Total funding: $596,885
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Characterisation of TCPTP as a tumour suppressorCharacterisation of TCPTP as a tumour suppressor
Lay Description (from application):
Breast cancer is the most frequent malignancy among women, with an estimated 1 million new cases per year
worldwide. A family of enzymes known as protein tyrosine kinases (PTKs) are fundamental in the initiation
and progression of tumour growth and they are frequently hyperactivated in breast cancer. This proposal will
examine whether inactivation of the enzyme known as TCPTP contributes to PTK hyperactivation and
tumorigenicity in breast cancer.
Research achievements (from final report):
Oxidative stress in obesity can contribute to the development of insulin resistance, a primary feature of type 2
diabetes. Although antioxidants have been touted as therapeutics, there is evidence that reactive oxygen species
(ROS) such as H2O2 can also promote insulin signalling. Hence it is possible that antioxidants might subvert
the physiological roles of H2O2. In this proposal we established that insulin promotes H2O2 generation in
skeletal muscle in vivo to enhance insulin signalling by inactivating protein phosphatases. We found that
general antioxidant administration to lean mice prevented insulin-induced H2O2 generation and signalling and
increased postprandial blood glucose levels. Our studies have established the importance of H2O2 in the
physiological insulin response in vivo and have highlighted the importance of targeted antioxidant approaches
in combating obesity-related diseases.
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
Tony.Tiagnis@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606609
CIA Name: Dr Richard Burke
Admin Inst: Monash University
Main RFCD: Cell Metabolism
Total funding: $268,329
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Intracellular trafficking of copper and platinum-based chemotherapueticsIntracellular trafficking of copper and
platinum-based chemotherapuetics
Lay Description (from application):
Platinum-based anti cancer drugs such as Cisplatin are effective against a number of cancers of the head, colon,
lungs and ovaries. Tumour resistance to these drugs has been closely associated with changes in genes that
control the movement of copper in and out of cells. We hypothesize that the same genes regulate distribution of
both copper and Cisplatin. By investigating these pathways, we aim to find ways to predict and prevent tumour
resistance to this important anti cancer treatment.
Research achievements (from final report):
Copper is an essential dietary nutrient that can also be highly toxic if not regulated correctly in the body. This
research used the vinegar fly Drosophila as a genetic model system to investigate how copper absorption,
distribution and excretion is controlled in animals. Several genes previously implicated in general cellular
protein trafficking pathways were found to play key roles in regulating the activity of known copper
transporters and thus influencing copper metabolism. In particular, localization of the uptake protein Ctr1was
found to be controlled by several different cellular processes; insufficient Ctr1 protein at the cell surface could
hinder absorption of dietary copper through the cells of the intestine, leading to copper deficiency. , Using
targeted genetic manipulation in the fly nervous system, it was also shown that both copper excess and copper
deficiency were detrimental to neuronal health, highlighting the importance of maintaining copper homeostasis
in the brain. This finding has implications for neurodegenerative disorders such as Alzheimer disease where
disturbed metal distribution may contribute to disease onset and progression., The final outcome of this
research was to establish a system for studying the pathogenic effects of disease-causing mutations. Due to the
high level of relatedness between human and Drosophila copper transport genes, mutations in the human
Menkes and Wilson disease genes can be replicated in the equivalent fly gene, allowing an in-depth analysis of
their effect on gene function. Many different mutations can be studied simultaneously and the efficacy of
potential therapeutic reagents evaluated rapidly at minimal cost.
Expected future outcomes:
The novel copper homeostasis genes discovered in this project will now be examined for roles in modifying the
onset and severity of copper-related disorders such as the inherited Menkes and Wilson disease and sporadic
Alzheimer disease. Pharmacological reagents that target these genetic risk factors can be investigated for
therapeutic potential.
Name of contact:
Richard Burke
Email/Phone no. of contact:
richard.burke@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606621
CIA Name: Prof Christina Mitchell
Admin Inst: Monash University
Main RFCD: Cancer Cell Biology
Total funding: $611,032
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Role of the inositol polyphosphate 4-phosphatase type 2 in human breast cancerRole of the inositol
polyphosphate 4-phosphatase type 2 in human breast cancer
Lay Description (from application):
Breast cancer is the most invasive cancer in females, affecting 1 in 9 women before the age of 85. Normally
cells only divide when they receive a stimulus from a hormone or growth factor. The PI3K pathway responds
to these stimuli and has been implicated in cancer when cells divide uncontrollably and invade surrounding
tissue. We have identified a potential cancer suppressing gene, 4-ptase-2 that turns off the PI3K growth signals.
We aim to characterize the role of 4-ptase-2 in breast cancer.
Research achievements (from final report):
Australian women have a one in eight risk of developing breast cancer during their lifetime. Cancer occurs
when cells undergo uncontrolled division and invasion into the surrounding tissues. Normally, cells only divide
in response to external stimuli such as hormones or growth factors which generate a series of signals inside the
cell. The PI3-kinase pathway is one signalling system which is activated in response to growth factor
stimulation. This pathway has been implicated in many human cancers including breast cancer. Stimulation of
this pathway leads to activation of a protein known as Akt which promotes cell transformation, a process cells
undergo as they become malignant., All cells which contain PI3-kinase also have enzymes which act to oppose
and switch off PI3-kinase generated signals. We have characterised an enzyme known as INPP4B and shown
that it specifically switches off PI3-kinase signals. Reducing the amount of INPP4B in breast cancer cells
promoted cell growth and transformation and led to increased tumour formation in mice. In contrast, increasing
INPP4B levels in breast cancer cells reduced Akt activation and cell transformation. Analysis of human breast
cancer samples revealed that INPP4B expression is lost in ~80% of basal-like tumours which are a type of
breast cancer with limited treatment options and poor prognosis. This study has provided evidence that INPP4B
acts as a tumour suppressor and that breast cancers with loss of INPP4B may be candidates for treatment with
PI3-kinase pathway inhibitors.
Expected future outcomes:
We have identified a protein which interacts with INPP4B and is also associated with breast cancer. We will
examine whether these two proteins are co-expressed in human breast cancer samples and will determine the
functional consequences of the interaction on cell transformation.
Name of contact:
Christina Mitchell
Email/Phone no. of contact:
christina.mitchell@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606931
Start Year: 2010
CIA Name: Prof Paul Hertzog
End Year: 2012
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Characterisation of Biological Macromolecules
Total funding: $517,990
Title of research award:
Structural characterisation function analyses of type I interferon-receptor interactionsStructural characterisation
function analyses of type I interferon-receptor interactions
Lay Description (from application):
The interferons are an essential component of the body's response to infectious and inflammatory disease and
cancer. In order to design the best therapeutic approaches to modulate interferon activity, we need a defined
understanding of how IFN binds to its receptor on target cells and activates its functions. This project will
characterize these interactions in cells, mice and molecules with x-ray crystallography and the synchrotron to
solve the structure and facilitate informed drug design.
Research achievements (from final report):
The innate immune system is the first-line of defense against infection in species as broadly diverse as humans,
plants and invertebrates. It comprises a diversity of cells and molecules, which act in concert to prepare the
adaptive immune response for a more sophisticated defense against invading germs. Our studies focused on
one of the key molecular interactions of the innate immune system: the binding of type I interferon proteins
(IFNs) to their cellular receptor, called IFNAR. Using the Australian Synchrotron, we solved the crystal
structure of this interaction. Our research also illuminated the cellular events downstream of this binding event.
In this study, we examined members of the type I IFN family which bind with different affinities to the two
components of the IFNAR receptor, IFNAR1 and IFNAR2. In our major publication in the Nature
Immunology Journal, we showed that IFN Beta uniquely and specifically binds to IFNAR1, independent of
IFNAR2, and that it activates a group of genes distinct from those traditionally activated by IFN Alpha's
interaction with IFNAR. Revealing the structure of IFNAR bound to IFN Beta, as well as the downstream
genes activated, provides a molecular basis for the different activities of members of the type I IFN family, and
may allow for refinement of IFN therapy. Our findings have significance for the use IFNs administered
therapeutically to treat chronic viral infections, cancer and multiple sclerosis.
Expected future outcomes:
On the basis of this research, we will examine in closer detail the signature of genes activated by IFN Beta's
interaction with IFNAR1.
Name of contact:
Prof Paul Hertzog
Email/Phone no. of contact:
Paul.Hertzog@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 628365
CIA Name: Prof Stephen Jane
Admin Inst: Monash University
Main RFCD: Dermatology
Total funding: $591,997
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Identification and characterization of a novel tumor suppressorIdentification and characterization of a novel
tumor suppressor
Lay Description (from application):
Australia has the highest rate of skin cancer in the world, with over 380,000 people diagnosed every year. Of
these, over 370,000 have non-melanoma skin cancers including squamous cell carcinoma and basal cell
carcinoma. Our laboratory has identified a gene in mice that protects animals from squamous cell cancer. The
studies proposed in this grant examine the mechanisms underpinning this protective role and may have
important implications for the prevention of skin cancers in humans.
Research achievements (from final report):
Australia has the highest rate of skin cancer in the world, with over 380,000 people diagnosed every year. Of
these, approximately 370,000 have non-melanoma skin cancers including squamous cell carcinoma (SCC), one
of the most aggressive forms. In this project we have identified the Grhl3 gene as a major tumour suppressor in
humans and mice that when damaged leads to the development of SCC. More significantly, we have defined
how Grhl3 loss triggers cancer development and we went on to unravel the entire signalling pathway that
underpins SCC in humans and mice, establishing a new paradigm for how this aggressive tumour arises. This
exciting work has been communicated in several international conferences focused on skin cancer and the
characterised signalling pathway, and published in the premier journal Cancer Cell. Our research has paved the
way for new preventative and therapeutic approaches for SCC that we are currently evaluating in pre-clinical
mouse models. In parallel, an integral role for Grhl3 has emerged leading to the extension of our findings into
SCC derived from multiple tissue origins, including head and neck and oesophagus. Our mouse models of
these diseases closely mirror the pathophysiology of SCC in humans, and as such, represent a unique resource
for assessing different therapeutical interventions. Future plans also centre on identifying the cell of origin of
SCC, which is critical in the development of methods for early diagnosis and treatment. Eventually, outcomes
from our studies could rapidly translate into clinical practice.
Expected future outcomes:
Future studies aim to trial specific drugs to determine their efficacy in a validated in vivo preclinical mouse
model. We anticipate that future results could rapidly translate into clinical outcomes, as some class of drugs
targeting the characterised signalling is already in clinical use for a range of tumours.
Name of contact:
Charbel Darido
Email/Phone no. of contact:
stephen.jane@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 628367
CIA Name: Dr Christopher Slape
Admin Inst: Monash University
Main RFCD: Haemotology
Total funding: $351,503
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Molecular analysis of myelodysplasia in the Nup98HoxD13 mouse modelMolecular analysis of
myelodysplasia in the Nup98HoxD13 mouse model
Lay Description (from application):
Myelodysplastic syndrome is a preleukemic condition which is poorly understood and occuring at an
increasing frequency. Unfortunately no targeted therapy exists. Two features of the disease are abnormal gene
expression and abnormal cell death. We have a uniquely accurate model of this disease, and we plan to use it to
investigate these two phenomena which will lead to greater understanding of the disease and new molecular
targets for therapeutic agents to be developed and tested in our model.
Research achievements (from final report):
This work overturned two preconceptions about myelodysplasia and the increased cell death that occurs in the
blood cells of patients with this disease. Firstly, the molecular pathway by which the cell death occurs has
traditionally been assumed to be the "extrinsic" pathway, whereas we show that it is in fact the "intrinsic"
pathway. This has implications for the types of molecules to target when designing therapies for
myelodysplasia. Secondly, we showed that the cell death, traditionally viewed as a protective mechanism
against the development of leukemia, is in fact a driver of the transformation to leukemia and not protective.
This also has major implications for therapy: whereas in most cancers the goal is to eliminate the diseased
cells, in myelodysplasia patients may fare better under treatment designed to keep their "diseased" cells alive.
Expected future outcomes:
We expect the publication of a further original research manuscript featuring the work of the two post-graduate
students who have contributed to this project. This publication will detail a further investigation of the
mechanism of cell death in myelodysplasia.
Name of contact:
Christopher Slape
Email/Phone no. of contact:
christopher.slape@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 637395
Start Year: 2010
CIA Name: Prof Graham Lieschke
End Year: 2013
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Gene Expression (incl. Microarray and other genome-wide approaches)
Total funding: $439,814
Title of research award:
A new BTB-ZF family transcription factor required in development and dysregulated in malignant diseaseA
new BTB-ZF family transcription factor required in development and dysregulated in malignant disease
Lay Description (from application):
We are studying the function and biology of a novel gene that looks like a generegulator. We generated a
zebrafish mutant with defective myeloid development, and we found this gene causes the defect. This mutant
fish provides a handle on the biological function of the gene in development. This gene has the hallmarks of a
transcription factor and we will study how it regulates other genes, and how it may be a target for treatment of
several cancers in which expression of this gene is activated.
Research achievements (from final report):
A zebrafish mutant identified because it had defective white blood cell development was studied. Little was
previously known about the gene that is mutated in this mutant. These studies confirmed that the gene is
required for the development of one white blood cell type (neutrophils) but not another (macrophages),
indicating a lineage-specific function for the gene. The structure-function of the gene has been studied. We
built new reagents so that the gene could be studied biochemically. Using biochemical approaches, other
proteins that bind to this new protein were identified, which point to the molecular pathways which are directly
regulated by it and help understand how it exerts its function. These studies point the way to understanding
several possible roles for this gene in different diseases. One binding partner is important in liver cancer,
adding to the evidence that this new gene might be important in liver cancer. Another binding partner is one of
a group of genes that are important in diseases with faulty blood cell formation, providing a clue how this new
gene might contribute to blood cell diseases.
Expected future outcomes:
Further studies are expected to cast light on the molecular pathways regulated by this new gene that account for
its effects on white blood cell development. A second line of research is probing the role of this gene in liver
cancer.
Nam