Research Projects 2012
Title of Project
THERAPEUTIC APPROACH TO TARGET GLIOMA STEM
CELLS USING THE WNT ANTAGONIST sFRP4: METABOLIC
STATE OF CANCER STEM CELLS AND NONTUMORIGENIC
CELLS
Major CHIRI theme(s)
Biomedical and Clinical Sciences
Program theme
Metabolic Health
Start date
Chief Supervisor
Other Supervisors
October 2012
Professor Arun Dharmarajan
Dr Kevin Keane and Professor Philip Newsholme
Project outline
(For example
background, aim,
methodology etc)
The concept of Cancer Stem Cells (CSC) has gained considerable attention
in various solid tumors including glioblastoma, the most common primary
brain tumor. This sub-population of tumor cells has been intensively
investigated and their role in therapy-resistance as well as tumor recurrence
has been demonstrated. Development of therapeutic strategies that target
CSCs and also the tumor bulk is an emerging approach to treat patients
suffering from primary brain tumors. We hypothesize that the metabolic
state of glioma CSCs differs from that of bulk tumour cell and normal cell
populations. To address this, we will be investigating the effect of the Wnt
pathway inhibitor, secreted frizzled receptor protein 4 (sFRP4) on ATP and
glucose metabolism in a panel of glioma cell lines and cell lines of other
tumours.
Initial studies have shown that sFRP4, which has anti-angiogenic and proapoptotic properties, can kill glioma stem cells as well as tumor bulk cells.
We found that this naturally occurring protein had minimal effect on
normal cells and normal stem cells, but was cytotoxic to tumour cells and
the cells that initiated the tumor, namely the CSC. Furthermore, sFRP4
could sensitise these cells to chemotherapeutic regimen. An important
component of Wnt signaling is glycogen synthase kinase 3-beta (GSK-3).
This enzyme is a key regulator of -catenin levels and is inhibited by Wntmediated activation of Dishevelled. GSK-3 plays a central role in
regulation of glycogen synthesis and consequently glucose metabolism.
Since normal, tumour and CSC cell metabolism is very different, we
propose to investigate GSK-3 as a means to fully elucidate the mechanism
of action of the newly discovered agent, sFRP4. This protein and its
individual domains will be useful for the development of new therapeutics
for targeted therapy for cancer stem cells. However, the following studies
need to be performed to further develop sFRP4 into a viable CSC targeting
therapy Determine the effect of sFRP4 in inducing chemosensitivity to
different drugs and identify the best drug regimen to be studied.
 Study the efficacy in destroying non-stem cells and stem cells of the
tumor.
 Study the metabolic state of the cancer stem cells and non-cancer
stem cells by determining ATP and glucose metabolism.
 Examine the interplay between GSK-3beta and sFRP4 in CSC
metabolism and cell death.
Methodology. Cell biology, molecular biology techniques, apoptosis assays, Invitro cell culture, and isolation of cancer stem cells
Project 2: Optimising Tissue Engineering
Project Background
Many tissues in adult mammals do not regenerate effectively after
injury or disease so new cell and tissue therapies are being
developed to improve repair and prevent disease progression. We
have produced vascularised tissues in rats by combining human
stem cells with matrix materials and a vascular supply. The following
projects are aimed to optimize this tissue engineering process and
move towards a clinical application.
The areas of research include:
1) Promoting tissue formation through angiogenesis. Stem cell
sources of angiogenic growth factors will be investigated for their
ability to promote tissue formation in vivo by tissue engineering. The
contribution of various adult stem cell populations to promoting
angiogenesis in engineered tissues and their regulation with matrix
scaffold materials will be investigated.
3) Engineered human tissue models for drug development and
toxicology. Functional tissue evaluation technologies will be
combined with methods for engineering vascularized organoids
suitable for drug testing. This project would be best suited to
graduates with pharmacology or bioengineering backgrounds.
Keywords
This project is
suitable for
Essential
Qualifications
Honours
Masters
PhD
X
BSc(Hons), MPhil, M.Sc or eligibility for enrolment as an HDR student.
Essential skills
Molecular/Cell Biology
Funding
Postgraduate scholarship is required for M.Sc;PhD. Some funds are available.
Additional grants are being prepared.
a.dharmarajan@curtin.edu.au
Contact for further
information