SAHMRI Cancer theme
Background on the theme: please click here.
1.
Topic: Ph-Like ALL in Adults and Children
Project: Optimising detection assays using RQ-PCR (TLDA card) to identify
novel druggable targets in suspected cases of Ph like ALL.
Acute Lymphoblastic Leukaemia (ALL) remains the leading cause of cancerrelated death in children and young people. The outcomes for adults
diagnosed with ALL are poor. A comprehensive understanding of the genetic
factors that influence leukaemogenesis and disease relapse are required to
guide the development of new therapeutic approaches. Recently a new
subtype of high risk ALL has been identified which is associated with the
presence of gene fusions that activate kinase, cytokine and other signaling
pathways. This subtype of ALL has been termed Ph-like (Philadelphia like).
The clinical importance and urgency of these findings is that many of these
fusions are likely treatable using drugs which are currently available in the
clinic, and as such have known safety profiles. Identification of these fusions
in individual patients will likely shift the treatment paradigm in this high-risk
cohort of patients to incorporate rational strategies using targeted therapies.
Anecdotal cases treated with targeted therapies to date have shown excellent
responses.
We have established screening tools based on phospho-flow cytometric
signaling, candidate PCR, sequencing and candidate gene expression
profiling using Taqman Low Density Arrays (TLDA cards) to detect likely
cases of Ph-like ALL. Discovery of new fusions is performed using mRNASeq.
While this is a thorough approach it is costly and time consuming. Our aim is
to streamline our screening approach such that many of the gene fusions
identified to date can be incorporated into an up-front “one-step” TLDA
screen. Establishing these new screening cards requires extensive testing of
relevant primer pairs and detection probes. This project will incorporate the
designing of gene primers and probes, and the testing of these on transduced
cell lines and primary patient material from known positive and negative Phlike cases. This project is an important step in the development of a new and
rapid screening approach for these patients in dire need of improved
therapeutic approaches.
2.
Topic: Gene Expression Profiling of Leukaemic Colonies
in CML
Project: Deep sequencing of Leukaemic colonies to assess key changes in
expression in Stem and Progenitor Cells in response to targeted therapies.
Tyrosine kinase inhibitors (TKIs) have set the current paradigm for treatment
of chronic myeloid leukaemia (CML), which is characterized by the
Philadelphia chromosome. This results from a balanced reciprocal
translocation of the long arms of chromosomes 9 and 22: t(9;22)(q34;q11)
giving rise to the BCR-ABL1 fusion gene which translates a constitutively
active tyrosine kinase, known to be causative of CML. While the majority of
CML patients achieve a good response to TKI therapy, some are overtly
refractory to therapy and others develop resistance. Of those patients who
respond well, only ~15% of all patients started on imatinib maintain deep
responses and can attempt a trial of TKI cessation. Surprisingly only 35-40%
of this group of patients remains disease free off of therapy, suggesting that in
only a small group of patients TKI therapy, which directly targets the Bcr-Abl
protein is able to “cure” the patient. The likely source of relapse off therapy is
the leukaemic stem cell (LSC), which may lie dormant in the presence of TKI,
but be mobilized in the absence of drug. Equally immunological factors may
play a significant role. Little is known about the gene expression profile of
LSC, largely because of the difficulty of performing deep sequencing on small
cell numbers. Equally, little is known about the immunological
factors/cytokines that may act to either support LSC or maintain a host versus
leukaemia effect. Lifelong TKI therapy is associated with drug related
“nuisance” toxicities and poses a significant financial burden to the PBS in
Australia.
We have recently purchased a C1 (Biomark) single cell/small cell number
deep sequencer and will be establishing this technology to address the above
questions. This project will involve establishing colonies from LSC and
progenitor cells and interrogating the differentially expressed genes
(leukaemic and immunological) between patients who relapse off therapy and
those who maintain treatment free remission. It is envisaged that genes
identified may provide guidance for future combinational therapeutic
approaches to augment treatment free remission in CML patients.
3.
Investigating Resistance Mechanisms to TKIs
Project: Investigating adherence in vitro as a cause/effect of overt resistance
in TKI treated BCR-ABL1+ cell lines.
We have established many BCR-ABL+ cell line models of TKI resistance. In
some of these lines we have observed cell adherence occurs during the
development of overt resistance. While the reasons for this adherence remain
to be determined we have demonstrated that in most cases it is associated
with the expression of the receptor tyrosine kinase Axl. It remains unclear
whether Axl expression is a cause or effect of resistance and indeed what its
specific role may be. It is possible that Axl results in cytoskeletal changes, but
equally it may be involved in recruitment of various adhesion molecules. The
reverse may also be true. Assessing the expression of adhesion molecules is
difficult using standard approaches such as flow cytometry as this requires
mobilisation of the adherent cells and thus a disruption of the adhesive
mechanisms.
Through an ACRF grant we have recently purchased a laser scanning
cytometer (LSC), which will enable the visualization and quantitation of
adhesion molecules in situ, using laser capture and time lapse imaging.
This project will involve the establishment of this approach to dissect the role
of cell adhesion in TKI resistance. The importance of this project is predicated
on our hypothesis that the changes that we are observing in culture are likely
analogous to the changes which occur in the marrow niche in vivo. We will
incorporate inhibitors of various proteins such as Axl, and others identified in
our screen to assess the relevance of receptor inhibition in reversing TKI
resistance.
Aboriginal Health theme
Background on the theme: please click here.
1. Cancer Data and Aboriginal Disparities (CanDAD)
The project seeks to develop an integrated, comprehensive cancer monitoring
system with a particular focus on Aboriginal people in SA that will integrate
cancer registry, hospital, radiotherapy, pharmacy, clinical, screening and
health insurance data to comprehensively monitor cancer incidence trends,
cancer management and survival. Uniquely, the data system will incorporate
Aboriginal patients’ experiences with cancer services to guide continuous
service improvement, community engagement, advocacy and outcomes
research, providing data infrastructure for health services, population
research, and for training Aboriginal (and non-Aboriginal) researchers. The
purposeful linkage of accurate and complete registry and administrative data
alongside narratives of Aboriginal people with cancer will facilitate
assessment of existing service quality and appropriateness, secular trends in
cancer risk, burden and determinants, will highlight areas of immediate need
and provide a robust system for performance monitoring and evaluation.
The aims of CanDAD are to develop an advanced cancer monitoring system
that:
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Improves cancer diagnosis, treatment and survival among Aboriginal
people;
Decreases the disparity between Aboriginal and non-Aboriginal peoples’
access to cancer prevention, screening and treatment; and
Improves the health service experiences of Aboriginal people at risk of, or
diagnosed with, cancer.
The summer scholarship recipient would be supported by the CanDAD
research team in conducting a scoping review that would contribute both to
the overall of topics that could be negotiated including:
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The uses of cancer registries internationally as vehicles for service
improvement and research
The collection and use of patient recorded outcome measures.
Experiences of Aboriginal people in correctional facilities who undergo
treatment for cancer
Experiences of Aboriginal young people with cancer services.
2. Potentially preventable hospital encounters among
Aboriginal South Australians
What do we know?
 A social gradient exists in the distribution of Potentially preventable
hospital inpatient stays generally
 Aboriginal South Australians are over-represented in potentially
preventable admissions (PPAs) to public hospitals
 Aboriginal South Australians are also more likely to experience multiple
PPAs in a given period of time
 Other health outcome indicators show evidence of a synergy between
area level socio-economic position and remoteness.
Question
 Does such a synergy exist between ecological risk factors for aspects of
hospitalisation, as a proxy for morbidity in the community?
 Will this synergy manifest as gradients within gradients? (i.e. different
PPA rates by (advantage)/disadvantage in Urban, Regional and Remote
settings?)
OUTPUTS (from the work)
 A summary paper (as above) – potential journals: International Journal for
Equity in Health; BMC Health Services Research; International Journal of
Indigenous Health; Health & Place;
 Report with fuller descriptions within the Landscape Project;
 Conference/seminar/grand round presentation(s) – a necessary and
valuable clarifying process for testing and gaining feedback on the
developing paper;
 There would be potential to do a further paper on age specific rates, the
types of conditions experienced, and the relative per capita frequency of
admissions associated with these.
3. Assisting with a Systematic Literature Review
Aboriginal and Torres Strait Islander peoples’ perceptions of quality of
life and wellbeing and how they are measured: A systematic review.
The objective of this review is to:
1. Identify tools used to measure quality of life and wellbeing in Aboriginal
and Torres Strait Islander Australians peoples.
2. Identify and synthesize Aboriginal and Torres Strait Islander peoples’
perceptions of quality of life and wellbeing
The concept of quality of life (QoL) is recognized as being both
multidimensional and vague1. _ENREF_1 Theoretical conceptualisations of
QoL are diverse and make identification of a common description difficult. The
lack of consensus is due in part to the multi-disciplinary application of the
concept which is compounded by multiple interpretations and
measurements2.
The use of western diagnostic tools to measure Indigenous peoples’ QoL has
implications for Indigenous peoples generally14 and for Aboriginal and Torres
Strait Islander peoples specifically. Unlike western cultures whose
understandings and perceptions of health and wellbeing are derived from a
biomedical model regarding physical functioning and perceptions of health15.
Australian Aboriginal and Torres Strait Islander peoples’ view of health
pervades the social and cultural context in which many live and their ways of
being16.
While there have been a number of studies which have attempted to
conceptualise QoL and wellbeing from Aboriginal and Torres Strait Islander
peoples’ perspectives, to our knowledge this is the first systematic literature
review which specifically aims to bring together and better understand the
findings from these studies. This systematic literature review, therefore, will
focus on understanding Australian Aboriginal and Torres Strait Islander
peoples’ definition of QoL inclusive of wellbeing. In addition, the systematic
literature review will also identify the instruments and/or measures that have
already been specifically developed to measure Australian Aboriginal and
Torres Strait Islander peoples’ QoL. We are offering a summer school
participant with an opportunity to work with a team of researchers who are
undertaking this systematic literature review.
4. Assisting with Analysing and Interpreting Qualitative Data
Kanyini Qualitative Study
The Kanyini Vascular Collaboration (KVC) was established by Aboriginal and
Torres Strait Islanders as well as non-Indigenous health researchers, policy
advisors, health economists, clinicians and community controlled health
services with the aim of improving health outcomes for Aboriginal and Torres
Strait Islander peoples (www.kvc.org.au). The Kanyini Qualitative Study
(KQS) is the second project in a series of discrete yet inter-related studies
conducted by KVC with Aboriginal and Torres Strait Islander communities and
primary healthcare partners in New South Wales (NSW), Central Australia
(including partners within the Northern Territory, Western Australia and South
Australia) (CA), and Queensland (Qld). In particular, the KQS was designed to
explore the principal barriers to and enablers of chronic disease care, in order
to inform an understanding of what better systems of care might look like for
Aboriginal and Torres Strait Islander populations.
Specifically, the KQS was designed to address the following research
questions:
1. What frames Aboriginal and/or Torres Strait Islander Australians’
engagement with care?
2. What does it mean to be looked after properly?
3. What are Aboriginal and/or Torres Strait Islander Australians’ experiences
of care for chronic disease?
4. What are the primary barriers to and enablers of care for Aboriginal and/or
Torres Strait Islander Australians with chronic disease and their families?
5. How do we develop better systems of care for Aboriginal and/or Torres
Strait Islander Australians?
From July 2008 to February 2010, semi-structured interviews were conducted
with 223 participants, 126 of whom were Aboriginal and/or Torres Strait
Islander peoples with and without chronic disease, and 97 of whom were
Indigenous and non-Indigenous health practitioners, health service
management or administrative staff (health providers).
Initial analysis of this database has already focused on a number of questions
including why Aboriginal and Torres Strait Islander peoples choose to engage
with care, what does care mean in this context and what are the systems
issues which impact on the way in which care is provided. However, there are
a number of other questions, which still require attention. We are offering an
opportunity for a summer school participant to work with experienced
qualitative researchers in order to undertake a further analysis and
interpretation of this database with a focus on these additional questions.