Download 2014 Postgraduate and Honours Cancer Research Projects 2014 Peter Mac Student Projects

2014 Postgraduate and Honours
Cancer Research Projects
2014 Peter Mac Student Projects
Page 1
Contents
Cancer Research Overview
The following pages highlight some of the projects available
for future students in 2014. If you are interested in a particular
project, use the contact details to follow up with the listed
supervisors to learn more about the project.
Peter Mac’s commitment to research is based on the belief that treatment informed by
research, and research informed by treatment, is the key to progressing better cancer care.
PROJECT DESCRIPTIONS BY RESEARCH PROGRAM
Tumour Angiogenesis Program
page 5
Oncogenic Signalling and Growth Control Program page 7
Cancer Genomics and Genetics Program
page 9
Cancer Therapeutics Program
page 15
Cancer Immunology Program
page 18
Cancer Cell Biology Program
page 20
Familial Cancer Centre
page 25
Research Education Program
page 26
For over 60 years, Peter Mac has been providing high quality treatment and multidisciplinary care for cancer patients and their
families. It houses Australia’s largest and most progressive cancer research group, one of only a handful of sites outside the United
States where scientists and clinicians work side-by-side. Cancer is a complex set of diseases, and modern cancer research
institutes such as Peter Mac conduct research that covers a diversity of topics that range from laboratory-based studies into the
fundamental mechanisms of cell growth, translational studies that seek more accurate cancer diagnosis, clinical trials with novel
treatments, and research aimed to improve supportive care.
The proximity and strong collaborative links of clinicians and scientists provides unique opportunities for medical advances to be
moved from the ‘bench to the bedside’ and for clinically orientated questions to guide our research agenda. As such, our research
programs are having a profound impact on the understanding of cancer biology and are leading to more effective and individualised
patient care.
Why study at Peter Mac?
Collaborative interaction with national and international peers is a lynchpin of any vibrant program. Peter Mac is continually seeking
to work with the best worldwide and the world’s best are increasingly seeking out Peter Mac researchers to interact with.
In speaking to current and past researchers and students, it is immediately evident that the two factors most strongly influencing
their decision to join and stay at Peter Mac are firstly, the opportunity to be mentored by a strong and collegiate group of senior
researchers and secondly, the superb research infrastructure that enables them to perform virtually any type of experiment they
require at affordable cost. This is a strong vindication of our strategy of identifying, seeding and supporting the growth of an enabling
environment, both in terms of talented senior personnel and first-class research infrastructure.
Research Structure
Cancer Research Division
The Cancer Research Division at Peter Mac is home to over
400 laboratory-based scientists and support staff, including
approximately 100 higher degree (mainly PhD) and Honours
students. Supported by nine core technology platforms,
our research laboratories are organized into six programs of
laboratory-based research and translational research:
• Cancer Cell Biology
• Cancer Therapeutics
• Oncogenic Signalling and Growth Control
• Cancer Genetics & Genomics
• Cancer Immunology
• Tumour Angiogenesis
Our core facilities and platform technologies are the backbone
of the division and ensure that the researchers are outfitted with
the equipment and expertise needed to facilitate their research.
An important role of the Platform Technologies Core Groups is to
also identify, import, and develop new technologies.
Clinical Research
Peter Mac is proud of its long history of involvement in clinical
research. The structure of clinical services at Peter Mac fosters
an environment in which clinicians from various specialties can
work together with allied health and supportive care staff on
clinical research projects with a disease-specific focus.
Research in the clinical services are structured into the following
areas:
Cancer Medicine Prof. John Zalcberg
[email protected]
Radiation Oncology
Assoc Prof Trevor Leong
[email protected]
2014 Peter Mac Student Projects
Page 2
2014 Peter Mac Student Projects
Cancer Surgery Assoc. Prof. Alexander Heriot
[email protected]
Breast
Assoc. Prof. Boon Chua [email protected]
Colorectal
Assoc. Prof. Craig Lynch [email protected]
Gynae-oncology Assoc. Prof. Kailash Narayan [email protected]
Haematology Prof. John Seymour [email protected]
Head and Neck Assoc. Prof. June Corry [email protected]
Lung Prof. David Ball [email protected]
Medical Oncology
Assoc Prof Danny Rischin
[email protected]
Melanoma and Skin Assoc. Prof. Michael Henderson & Prof Grant McArthur
[email protected] & [email protected]
Paediatric, and Late Effects Dr Greg Wheeler [email protected]
Sarcoma
Prof. Peter Choong
[email protected]
Upper Gastrointestinal Assoc. Prof. Michael Michael [email protected]
Uro-oncology
Dr Farshad Foroudi [email protected]
Cancer Imaging
Prof Rod Hicks
[email protected]
Familial Cancer Research Dr Gilian Mitchell
[email protected]
Page 3
TUMOUR ANGIOGENESIS PROGRAM
Platform Technologies
Peter Mac has platform technologies that underpin our
research and allow Peter Mac researchers to be internationally
competitive in an increasingly technology-driven environment.
Peter Mac’s core technologies and expertise are also made
available to external researchers on a collaborative or costrecovery basis, thereby increasing research output in the wider
bioscience community. Key technologies at Peter Mac include:
Flow Cytometry and Cell Sorting This facility provides
researchers with access to state-of-the-art equipment and
expertise that enables isolation, separation and analysis of cell
populations based on their biological and therapeutic properties.
The facility offers multi-parameter flow cytometric analysis for
identifying rare populations of cells within complex mixtures such
as human bone marrow, and two fully supported fluorescent
activated cell sorting (FACS) instruments for isolating cells such
as blood progenitor cells under sterile conditions.
Molecular Genomics: Peter Mac has been the leading site
in Australia in the application of gene microarray technology for
predicting outcomes of human cancer or an individual’s likely
response to a given therapy. The facility operates three major
platforms; Illumina HiSeq 2500 (next-generation sequencer),
Nanostring nCounter Analysis System (digital analyser) and
Affymetrix GeneChip System (microarray).
Functional Genomics: The Victorian Centre for Functional
Genomics (VCFG) is the leading functional genomics facility
within Australia, enabling researchers to perform high throughput
genome-scale gene knockdown screens to identify novel
targets regulating cancer biology. The facility offers biomedical
researchers Australia-wide the ability to perform genome-wide or
custom boutique screens using multiple platforms: short hairpin
RNA (shRNA), small interfering RNA (siRNA), micro RNA (miRNA)
and, commencing in 2014, long non coding RNA (lncRNA).
Microscopy Imaging and Research. The facility provides
sophisticated microscopy equipment and software supported
by technical expertise to facilitate laboratory research integral
to a wide range of cancer research projects. This is a worldclass facility encompassing all aspects of microscopy such as
immunofluorescence, laser capture, confocal and transmission
electron microscopy.
Transgenic and SPF Facility. We currently breed and
maintain approximately 20,000 mice, representing over 130
different strains of transgenic and gene-targeted mice. Peter
Mac’s Animal Ethics Committee (AEC) has an important role in
overseeing the ethical conduct of any work involving the use
of animals for scientific purposes, conforming to the NHMRC
Australian Code of Practice for the Care and Use of Animals for
Scientific Purposes.
Molecular Pathology is a central platform to successful
translational research by providing robust Diagnostic molecular
analyses of tumours. Molecular Pathology at Peter Mac provides
diagnostic testing for familial breast and colorectal cancer, and
is a national reference centre for testing for specific mutations in
cancer samples.
Molecular Imaging. The Centre for Cancer Imaging is a
world leader in the clinical use of PET scanning in cancer. The
facility includes three chemists, contains a cyclotron, two small
animal PET scanners for translational research and automated
production facilities for a number of novel tracers. These tracers
provide the capacity to image diverse biological processes
including hypoxia, lipid synthesis, cell proliferation and amino
acid transport.
Biostatistics at Peter Mac is the leading biostatistical centre
focusing on cancer clinical trials in Australia. The centre provides
statistical expertise for national cancer trials groups including
the Trans Tasman Radiation Oncology Group (TROG) and the
Australasian Leukaemia and Lymphoma Study Group (ALLG).
Clinical research nurse core. Peter Mac currently has
a team of research nurses to support a sophisticated clinical
and translational research program. These nurses provide
necessary skills to coordinate phase I first-in-man clinical trials
involving complex procedures such as tumor biopsies for
evaluation of molecular targets, serial PET scans and complex
pharmacokinetic sampling.
Heads: Associate Professor Marc Achen & Associate Professor Steven Stacker
A tumor establishes a blood supply by secreting proteins that attract the growth of blood vessels (angiogenesis) from surrounding tissue. This allows the tumor to grow more rapidly and to spread to distant sites in the body via the blood vasculature. This spread of
tumor cells is known as metastasis and is the most lethal aspect of cancer. We and others have shown that tumors also attract the
growth of lymphatic vessels (lymphangiogenesis) which facilitates metastatic spread via the lymphatics.
We seek to identify and characterize the signalling pathways which control tumor angiogenesis and lymphangiogenesis, with a view
to targeting them in the clinic to restrict the growth and spread of cancer. These pathways include those triggered by the vascular
endothelial growth factors (VEGFs) and VEGF receptors on blood vessels and lymphatics. This approach to cancer therapeutics has
previously given rise to therapeutic agents, including a neutralizing antibody targeting VEGF-A, known as Avastin (or bevacizumab).
Another focus of the laboratory is an alternative molecular signaling pathway involving the Wnt ligands and the Ryk receptor that is
thought to be important in cancer biology. This intriguing pathway is essential for embryonic development and may play a role in the
proliferation of cancer cells and tumor metastasis. A deeper understanding of this pathway will facilitate attempts to inhibit Wnt/Ryk
signaling in the setting of cancer. Our studies of signaling for tumor growth and metastasis involve technologies relating to molecular
biology, cell biology, protein chemistry, developmental biology and genetic models of disease.
DEFINING SIGNALLING PATHWAYS THAT CONTROL THE
RESPONSE OF ENDOTHELIUM TO CANCER THERAPY
Supervisors: Assoc. Prof. Steven Stacker, Dr. Michael Halford
The formation and alteration of blood and lymphatic vessels are
important for the growth and spread of spread of cancer. Targeting
the process of angiogenesis by blocking the action of vascular growth
factors with agents such as Avastin has already shown promise for
cancer therapy. To understand the response of endothelial cells to
cancer therapy, including biologicals, radiotherapy and chemotherapy
we are establishing screening systems using human endothelial cells
of blood vascular and lymphatic origin. These screens will involve
the introduction of a library of shRNAs followed by selection for
endothelial cell phenotypes with relevance to \various anti-cancer
therapeutic regimes.. Such screens will give insight into the signalling
pathways determining sensitivity and resistance to general anti-cancer
therapeutics and current anti-angiogenesis approaches.
This project will investigate a specific endothelial subset in combination
with a suitable anti-cancer treatment protocol, and rescue using a
library of shRNA from the Victorian Centre for Functional Genomics.
The student would identify and characterise specific genes, which
when perturbed, are involved in the rescue and these would be further
characterised using in vitro and in vivo assays of angiogenesis and/
or lymphangiogenesis that are established in the laboratory. This
information would form the basis for developing an understanding of the
complex signalling networks present in endothelial cells and how these
may be targeted in cancer.
During this project the student will develop skills including culture of
primary cells, in vitro cell and molecular biology assays, use of RNAi to
enable gene knockdown, and bioinformatics analysis. The project is
designed to isolate key molecules that control the response of blood
and lymphatic vessels to anti-cancer therapy. Further, the work is
intended to define molecules which may be developed as the targets
for biomarker assays with appropriate biotechnology collaborators.
Bioinformatics. The Bioinformatics facility at Peter Mac
crunches the huge volumes of data produced by the Molecular
Genomics facility and the Victorian Centre for Functional
Genomics through the provision of state-of-the-art open-source
software, as well as custom-made computational algorithms,
analysis pipelines and web interfaces designed specifically
for cancer research. The Bioinformatics facility is a complex
processing unit, turning vast masses of biological data into
interpretable information.
For more information about this project contact: Assoc. Prof. Steven
Stacker, Tel: +61 3 9656 5263, Email: [email protected]
UNDERSTANDING THE SIGNALING OF THE RYK GROWTH FACTOR
RECEPTOR IN CANCER
Supervisors: Assoc. Prof. Steven Stacker
Tissue Bank. Peter Mac has been a leader in the
development of sophisticated biospecimen and clinically
annotated cancer samples collection. We are the host institute
for the Australian Biospecimen Bank a federally funded project to
enable national cancer sample collection and facilitated access
to tissue resources. The Tissue bank provides researchers with
ethically collected, high quality human tissue, blood and data
samples for their investigative projects; it also supports clinical
trials at Peter Mac by processing and storing blood and tissue
specimens in accordance with trial-specific protocols
2014 Peter Mac Student Projects
http://www.petermac.org/research/conducting-research/tumour-angiogenesis
Ryk is a member of the growth factor receptor family which is critically
involved in signaling for correct mammalian development. Members
of this family are known to be key regulators of mammalian cell
proliferation, differentiation and migration and are therapeutic targets for
many human cancers. Ryk is a receptor for members of the Wnt family
of morphogens, and therefore provides a pivotal link between the Wnts
and cellular regulation. We have recently demonstrated the key role
that Ryk plays in non-canonical Wnt signaling via the planar cell polarity
(PCP) pathway (Macheda et al., Journal of Biological Chemistry, 2012).
This project will investigate the role of Ryk in human cancer by
identifying and characterising the biochemical signaling mechanisms
Page 4
2014 Peter Mac Student Projects
used to signal via the Ryk receptor and further characterising the
identity of extracellular liagnds for Ryk. The study will integrate the
use of a loxP-flanked Ryk knockin allele which allows for the inducible
deletion of the cytoplasmic domain in a mouse model. Further, a human
monoclonal antibody, developed in our laboratory, which blocks Wnt
binding by Ryk,, will be evaluated for activity against known ligands and
its efficacy in appropriate tumor models.
During the project the student will develop skills in analysis of in
vivo models, advanced cell and molecular biology techniques and
development of a humanized antibody suitable for pre-clinical testing.
For more information about this project contact: Assoc. Prof. Steven
Stacker, Tel: +61 3 9656 5263, Email: [email protected]
ROLE OF PROSTAGLANDINS IN TUMOR METASTASIS
Supervisors: Dr. Tara Karnezis, Assoc. Prof. Marc Achen and Assoc.
Prof. Steven Stacker
Lymphatic metastasis is a critical initial step in the spread of cancer.
Powerful lymphangiogenic growth factors such as vascular endothelial
growth factor (VEGF)-D and VEGF-C are secreted by some primary
tumors and are capable of altering existing lymphatic vessels,
generating new vessels in a process known as lymphangiogenesia,
facilitating tumor metastasis. We have recently shown the critical role
that VEGF-D plays in metastasis via the collecting lymphatic vessels
(Karnezis et al., Cancer Cell 2012), and that this process is dependent
on the prostaglandin signaling pathway which is sensitive to inhibition
by the group of drugs known as the Non-Steroidal Anti-Inflammatory
Drugs (NSAIDs).
The project will investigate the role of VEGF-D and VEGF-C in the
promotion of tumor metastasis and explore the biochemical and
biological mechanisms involved in this process. The student will use a
combination of in vitro and in vivo tumor models and further define the
regulation of metastasis. Furthermore, they will examine the effects of
a range of NSAIDs on tumor metastasis, and determine those most
effective at preventing tumor spread. During the project, the student
will develop a broad range of molecular and cell biology techniques,
including in vitro endothelial assays and in vivo tumor experiments and
evaluation of anti-cancer drugs by animal imaging.
For more information about this project contact: Assoc. Prof. Steven
Stacker, Tel: +61 3 9656 5263, Email: [email protected]
ROLE OF “WOUND HEALING PROTEINS” IN CANCER
Supervisors: Assoc. Prof. Marc Achen and Dr. Sophie Paquet-Fifield
Vascular endothelial growth factors (VEGFs) are secreted glycoproteins
which promote growth of bloods vessels (angiogenesis) and lymphatic
vessels (lymphangiogenesis) in cancer, and thereby drive tumor growth
and spread. VEGFs and their receptors are targets for various recentlyapproved anti-cancer therapeutics, including the antibody Avastin (also
known as Bevacizumab). VEGF-D is a member of the VEGF family that
promotes angiogenesis and lymphangiogenesis, and its expression in
human cancers can correlate with metastatic spread and poor patient
Page 5
outcome (see Achen et al., Cancer Cell 2005). Based on our studies of
VEGF-D function in cancer, we recently discovered that certain proteins
which regulate wound healing (“wound healing proteins”) also play key
roles in promoting the metastatic spread of cancer.
The aim of this project is to determine how these “wound healing
proteins” modulate the growth and spread of cancer, with a view to
developing diagnostic and therapeutic strategies based on targeting
these molecules. This project will provide experience in genetics,
molecular biology, microscopy, histology and physiology. It will lay the
foundation for translational studies designed to restrict the metastatic
spread of cancer.
For more information about this project contact: Assoc. Prof. Marc
Achen; Tel: 61-3-9656-5264; Email: [email protected]
TARGETING GROWTH FACTOR ACTIVATION IN CANCER
Supervisor: Assoc. Prof. Marc Achen
Angiogenesis, growth of lymphatic vessels (lymphangiogenesis),
immune suppression and recruitment of tumor stroma are important
features of cancer biology that are in part driven by protein growth
factors. Many of these growth factors are secreted from tumor cells
in inactive forms which require activation by proteases. For example,
we have shown that proteolytic activation of members of the vascular
endothelial growth factor (VEGF) family of proteins is an important step
in promoting tumor angiogenesis and lymphangiogenesis in cancer
which in turn facilitates tumor growth and spread. We have shown that
the proteases involved are members of the proprotein convertase (PC)
family of enzymes which also activate a range of other growth factors
with roles in cancer biology. These findings suggest that targeting
members of the PC family may be useful for restricting the growth
and spread of cancer. This project will explore the effect of targeting
individual members of the PC family on tumor growth and spread in
animal models. PCs in tumor cells or tumor stroma will be targeted by
siRNAs, small molecule inhibitors or other technologies and effects on
primary tumor growth and metastatic spread will be monitored. During
this project the student will develop skills in cell biology, biochemistry,
tissue culture and animal models of disease.
For more information about this project contact: Assoc. Prof. Marc
Achen; Tel: 61-3-9656-5264; Email: [email protected]
MOLECULAR ANALYSIS OF LYMPHOEDEMA, A COMMON
COMPLICATION OF SURGERY FOR BREAST CANCER
Supervisors: Assoc. Prof. Marc Achen, Assoc. Prof. Steven Stacker and
Dr. Sophie Paquet-Fifield
Lymphoedema is a problematic disease that arises from damage to
lymphatic vessels leading to swelling and dysfunction of limbs. It often
occurs after surgery for cancer involving removal of lymph nodes – an
example is the dramatic swelling of the arm in some women who have
undergone surgery for treatment of breast cancer. Lymphoedema can
be chronic and debilitating, and there is no effective treatment. Hence
there is a great need to understand the anatomical and molecular
features of lymphoedema to inform novel approaches for the diagnosis
and treatment of this condition. We have therefore developed novel
surgical approaches to model lymphoedema, from which we can
access tissues allowing us to identify key anatomical events and
molecular pathways causing the disease.
ONCOGENIC SIGNALLING AND GROWTH CONTROL PROGRAM The project involves analysis of these models at the histological and
molecular levels using histology, immunohistochemistry, microarray and
bioinformatics. Potential molecular targets for prognosis and treatment
will be validated in samples of human lymphoedema, and approaches
tested for efficacy in the animal models. This strategy will provide an
ideal platform for future translational work to develop these approaches
for the clinic. The project will provide experience in a broad range of
highly relevant techniques in biomedical research.
The Oncogenic Signalling and Growth Control Program consists of three groups (Pearson, Hannan and McArthur) with extensive and
complementary expertise in areas ranging from proteomics and protein chemistry, through signal transduction and cell biology to the
regulation of gene transcription and protein translation. A major focus of our work is in understanding the mechanisms of regulation of
ribosome biogenesis, and protein translation, and how these processes impact on differentiation and are corrupted in tumour cells. A
number of current projects employ state-of-the-art biochemistry, molecular and cell biology to characterize the basis of the regulation
of these fundamental processes.
For more information about this project contact: Assoc. Prof. Marc
Achen; Tel: 61-3-9656-5264; Email: [email protected]
AKT DRIVEN SENESCENCE AND CANCER
http://www.petermac.org/research/conducting-research/oncogenic-signalling-and-growth-control
Heads: Associate Professor Ross Hannan, Associate Professor Rick Pearson, Professor Grant McArthur
Supervisors: Dr. Kate Hannan, Assoc. Prof. Rick Pearson
UNDERSTANDING THE SIGNALING NETWORKS WITHIN
LYMPHATIC ENDOTHELIAL CELLS
Supervisors: Dr. Tara Karnezis, Assoc. Prof. Marc Achen and Assoc.
Prof. Steven Stacker
Lymphatic endothelial cells (LECs) line lymphatic vessels and are
essential control points for interaction with immune cells and proteins
contained within the lymphatic fluid that fills these vessels. LECs also
participate in the generation of new lymphatic vessels and remodeling
of preexisting vessels that occur during embryogenesis and in various
pathologies. To gain a detailed understanding of how LECs receive and
integrate signals from their environment, we have performed a genomewide siRNA screen to map their signaling networks.
This project will provide key biological and biochemical validation of
candidate genes identified during a genome-wide siRNA screen for
modifiers of LEC migration. Further, the project will allow the detailed
analysis of high content morphological data acquired during the
screen and provide a key comparison between functional data and
morphological changes seen with individual LEC or LEC monolayers.
The project will provide the unique opportunity to assess both novel
regulators of LEC activity and structure-function analysis within the LEC.
The student will develop skills in advanced cell and molecular biology,
including developing assay systems to study primary LEC. The project
will also integrate bioinformatics and cell morphometric analysis to allow
the correlation of functional data and cell morphology changes. Further,
collaborations within the Pathology Department of Peter Mac (Prof
Stephen Fox) will allow validation of these findings in human tissue.
For more information about this project contact: Assoc. Prof. Steven
Stacker, Tel: +61 3 9656 5263, Email: [email protected]
The PI3K/AKT/mTORC1 signalling pathway is a key regulator of
both senescence (irreversible cell cycle arrest) and the development
of cancer. We, and others, have shown that hyperactivation of the
pathway in normal cells leads to cellular senescence which effectively
acts as a “brake” on the progression to malignancy.
We hypothesise that specific genetic changes overcome this brake
and permit the increased cell proliferation and transformation required
for cancer development. We will utilize our well established model of
AKT-induced senescence in normal human cells mediated via a p53
and mTORC1-dependent mechanism (Astle et al, 2011, Oncogene).
Our data suggests that AKT: i) activates mTORC1 to enhance p53
translation and stability; and ii) results in nucleolar sequestration
of MDM2 via an unknown mechanism. Understanding the basis
of oncogene-induced senescence in normal cells and how this is
subverted in cancer cells will provide insight into the mechanism of
malignant transformation and how it can be effectively targeted. This
project aims to:
(1) Define the mechanism underlying AKT-induced senescence in
normal cells.
(2) Determine the genetic changes required to overcome AKT-induced
senescence.
This project will utilize cell culture, and techniques such as ribosome
profiling, immunoprecipitation, RT-PCR, siRNA screening, tandem
mass spectrometry, proteomics, transcription assays, IHC and western
analysis. The siRNA screen will use SMARTpool reagents in a 96 well
format platform which will be quantitated using a high throughput,
high content microscopy platform (Cellomics). Cell proliferation will be
assessed using DAPI and senescence using SAβGAL staining.
For more information about this project contact: Dr. Kate Hannan, Tel:
+61 3 9656 1279, Email: [email protected]; Assoc. Prof.
Rick Pearson, Tel: +61 3 9656 1247, Email: [email protected]
BIOCHEMICAL AND MOLECULAR DISSECTION OF THE
MECHANISMS CONTROLLING RIBOSOME BIOGENESIS BY THE
PI3K/AKT/mTORC1 NETWORK.
Supervisors: Dr. Kate Hannan, Assoc. Prof. Ross Hannan, Assoc. Prof.
Rick Pearson
Dysregulation of the PI3K/AKT/mTORC1 signaling pathway occurs
in a wide variety of cancers and is thought to play an essential role in
malignant transformation. The downstream actions of this pathway
to regulate ribosome biogenesis and translation are essential for its
oncogenic effects. The oncogene MYC, which is dysregulated in 1520% of human malignancy, interacts with PI3K/AKT/mTORC1 pathway
to form a super signalling network in malignancy.
We hypothesize that PI3K/AKT/mTORC1 and MYC cooperate during
malignancy to ensure ribosome biogenesis remains hard wired in
tumour cells. Our Science Signalling paper (Chan et al 2011) illustrated
MYC and PI3K/AKT/mTORC1 co-operation in the regulation of rDNA
transcription and ribosome biogenesis, thus the next step is to elucidate
the mechanism(s) involved which forms the basis for this project. This
project aims:
(1)To determine how the PI3K/AKT/mTORC1 module and MYC
cooperate and/or redundantly modulate rDNA transcription by Pol I.
2014 Peter Mac Student Projects
Page 6
2014 Peter Mac Student Projects
(2) To identify mechanisms by which PI3K/AKT/mTORC1 and MYC
pathways modulate Pol I elongation by candidate analysis and high
throughput functiona l genomics screens.
(3) To define the interactions between PI3K/AKT/mTORC1 and MYC
required for control of rDNA transcription in Em-MYC lymphoma cells in
vitro and in vivo.
This project will utilize cell culture and animal models of cancer,
and techniques such as RT-PCR, siRNA screening, proteomics,
transcription assays and western analysis.
For more information about this project contact: Dr. Kate Hannan, Tel:
+61 3 9656 1279, Email: [email protected]; Assoc. Prof.
Rick Pearson, Tel: +61 3 9656 1247, Email: rick.pearson@petermac.
org
METABOLIC CONTROL OF RIBOSOME BIOGENESIS BY PI3K/AKT/
MTOR AND MYC IN CANCER
Supervisors: Dr. Kate Hannan, Assoc. Prof. Rick Pearson
Ribosome biogenesis is the major energy consuming process in
proliferating cells and is rate limiting for the protein synthesis required
for cell growth and division. Consequently cells need to respond
efficiently and quickly to even subtle changes in nutrient levels, which
is highlighted by the metabolic switch observed in cancer cells thus
facilitating the elevated ribosome biogenesis required for increased
growth and proliferation.
We hypothesize that the PI3K/AKT/mTORC1 pathway and c-MYC
are critical for nutrient regulation of ribosome biogenesis. This is based
on three observations; i) glutaminolysis plays a critical role in nutrient
dependent control of mTORC1 activity and cell growth; ii) MYC plays
a critical role in controlling glutamine metabolism; and iii) MYC and
PI3K/AKT/mTORC1 signalling cooperate in controlling growth factor
dependent ribosome biogenesis. The following aims will investigate this
hypothesis
(1) Determine the effects of manipulating nutrient levels on the synthesis
of functional ribosomes and cell growth.
(2) Define the mechanism(s) of control of ribosome biogenesis in
response to changes in nutrient (and energy) levels.
(3) Define the requirement for nutrient signalling and/or glutaminolysis
in the regulation of ribosome biogenesis, cell growth and survival in EmMYC lymphoma cells in vitro an in vivo.
This project will utilize cell culture and animal models, and techniques
such as glucose/glutamine uptake assays, RT-PCR, apoptosis assays,
transfections, shRNA, metabolic labelling, PET image of whole mouse,
transcription assays, IHC and western analysis
For more information about this project contact: Dr. Kate Hannan, Tel:
+61 3 9656 1279, Email: [email protected]; Assoc. Prof.
Rick Pearson, Tel: +61 3 9656 1247, Email: rick.pearson@petermac.
org
ROLE OF AP-1 TRANSCRIPTION FACTORS IN CANCER
PROGRESSION
Supervisors: Dr Amardeep Dhillon, Assoc. Prof. Ross Hannan
The spread of tumours by invasion and metastasis is the major cause
of mortality in many types of cancers. These complex processes
require tumour cells to modify gene expression in order to adapt to
new environments and overcome physiological barriers maintaining
tissue homeostasis. The orchestration of these events is mediated by
Page 7
transcription factors embedded within specific oncogene or tumour
suppressor networks operating in the cell. One such factor is the
Activator Protein-1 (AP-1) complex, which regulates gene expression in
response to numerous physiological (e.g. growth factors, cytokines) and
pathological (e.g. oncogenes, stresses) stimuli. AP-1 is also a key point
of convergence for many cancer-associated signaling networks.
This project will investigate the mechanism of action of a number of the
candidates identified from the siRNA screen. We will use techniques
including but not limited to: cell culture, RNA interference, SDSPAGE and western blotting, real-time qRT-PCR, FACS analysis and
immunofluorescence to validate their role in blocking cancer cell growth,
and overcoming perturbations in ribosome biogenesis.
This project aims to identify transcriptional targets and gene expression
programs regulated by AP-1 in cancer cells. In addition the project
will also aims to identify signaling pathways and transcription factors
that cooperate with Fra-1 to control pro-malignant gene expression
programs. The work will involve a combination of genomic analyses,
bioinformatics, cell biological approaches and analysis of patient
tissue specimens. This research is expected to provide new insights
into how the expression of genes required for the spread of cancers
is orchestrated, and identify new therapeutic targets to impede the
progression of aggressive cancers.
For more information about this project contact: Dr. Amee George, Tel:
+61 3 9656 3758, Email: [email protected]; Assoc. Prof.
Ross Hannan, Tel: +61 3 9656 1747, Email: ross.hannan@petermac.
org
For more information about this project contact: Dr Amardeep Dhillon,
Tel: +61 3 9656 1279, Email: [email protected]; Assoc.
Prof. Ross Hannan, Tel: +61 3 9656 1747, Email: ross.hannan@
petermac.org
HOW THE FRA-1/AP-1 TRANSCRIPTION FACTOR CONTROLS
GENE EXPRESSION IN CANCER CELLS
Supervisors: Dr Amardeep Dhillon, Assoc. Prof. Ross Hannan
The epithelial to mesenchymal transition (EMT) is a process essential
for vertebrate development, involving concomitant loss of epithelial
homeostasis and appearance of mesenchymal traits in cells. Acquisition
of these traits can endow cancer cells with the ability to invade,
metastasize, self-renew, and become drug resistant. Understanding,
and subsequently disrupting, the mechanisms preserving cancer cells
in a mesenchymal state may therefore provide a potential strategy to
target aggressive cancers.
We recently discovered that the transcription factor Fra-1/AP-1 is
required to preserve mesenchymal traits in colorectal cancer cells
(CRCs), by directly binding and regulating expression of a clinicallyrelevant cohort of genes mediating EMT. This project aims to
understand how these actions of Fra-1 are mediated at the molecular
level. Specifically, we will test if binding of Fra-1 is required to maintain
chromatin environments that are permissive for transcription of EMTassociated genes. In addition, we will characterise the nature of Fra-1/
AP-1-associated chromatin remodelling factors involved in target gene
transcription. These studies will provide new insights into the molecular
mechanisms controlling cellular traits associated with aggressive forms
of CRC, and potentially other high-grade malignancies featuring Fra-1/
AP-1 overexpression.
For more information about this project contact: Dr Amardeep Dhillon,
Tel: +61 3 9656 1279, Email: [email protected]; Assoc.
Prof. Ross Hannan, Tel: +61 3 9656 1747, Email: ross.hannan@
petermac.org
INVESTIGATING HOW PERTUBATIONS IN RIBOSOME BIOGENESIS
INHIBIT CELLULAR GROWTH
Supervisors: Dr. Amee George, Assoc. Prof. Ross Hannan
Ribosome biogenesis is a key component in the synthesis of cellular
proteins, and is an absolute requirement for cellular growth and
proliferation. Perturbations in ribosome biogenesis, either by inhibiting
Pol I transcription (involved in ribosomal RNA synthesis), or defective
or absence of ribosomal proteins, leads to the activation of the
‘nucleolar surveillance pathway’, where HDM2/MDM2 is sequestered
by free ribosomal proteins, allowing p53 to become stabilised and
transcription of p53 target genes that cause cell cycle arrest, apoptosis
or senescence responses (Hein et al., Trends Mol Med 2013).
We have demonstrated that cancer cells are associated with
dysregulated ribosome biogenesis, and that targeting Pol I transcription
with a small molecule inhibitor (CX-5461) leads to p53-mediated
apoptosis of cancer cells, whilst having no effect on normal cells
(Bywater et al., Cancer Cell 2012). We have also demonstrated
that knockdown of ribosomal proteins, such as RPS19 (mutated in
Diamond-Blackfan anaemia) leads to p53-mediated cell cycle arrest.
We believe that the mechanism underlying both of these observations
is similar, i.e. due to nucleolar stress. However, much detail about
this process is still lacking. As such, we are currently performing a
genome-wide short interfering RNA (siRNA) (loss of function) screen
that is currently being performed in the Victorian Centre for Functional
Genomics at Petermac to identify candidates that when absent (i)
increase the activation of p53 and (ii) bypass the activation of p53 when
ribosome biogenesis is disturbed with RPS19 knockdown.
2014 Peter Mac Student Projects
REGULATION OF CHROMATIN REMODELING OF THE rRNA GENES
IN MOUSE EMBRYONIC STEM CELLS
Supervisors: Assoc. Prof. Ross Hannan and Dr. Nadine Hein
EPIGENETIC REGULATION OF POL I TRANSCRIPTION BY UBF
Supervisors: Assoc. Prof. Ross Hannan and Dr. Elaine Sanij
Transcription of the 200 copies of ribosomal RNA genes (rDNA) by RNA
Polymerase I (Pol I) is a fundamental rate-limiting step for growth and
proliferation. The Pol-1 specific nucleolar transcription factor UBF is
essential for maintaining the active chromatin state of ribosomal genes
(Sanij and Hannan, 2009). We have begun studies to examine the
following:
(1) Epigenetic mechanisms of UBF action: To define the effect
of decreased UBF expression on the chromatin status and Pol I
transcription. We will undertake a detailed structure function analysis
of UBF to differentiate the domains in this factor required for gene
activation and chromatin remodeling etc.
In somatic mammalian cells over 50% of the ~200 copies of the
rRNA genes are silenced though CpG methylation. Given that rRNA
gene transcription is limiting for growth silencing of half the rRNA
gene capacity seems counter intuitive. Interestingly there is an
increasing body of evidence to suggest that rDNA silencing is critical
not only for suppressing unwanted recombination within the rDNA
repeat and general nucleolar organization but also for controlling, to
some extent, general heterochromatin of the nucleus. For example,
in Drosophila mutants that are defective in the histone H3 Lys 9
(H3K9) methyltransferase Su(var)3-9 and other factors involved in
heterochromatin formation exhibit increased nucleolar fragmentation
and accumulation of extrachromosomal rDNA circles. In addition
to suppression of recombination, it appears that the perinucleolar
heterochromatin might serve as a distinct nuclear space with a primary
function in maintaining repressive chromatin states. Thus the reason
for the silencing of over 50% of the rRNA genes repeats in mammalian
cells is not clear. In our view it seems unlikely it is to simply to limit rRNA
synthesis rates and growth.
(2) Epigenetic regulation of Pol I transcription during differentiation
and development: To determine whether the decreased expression
of UBF is a prerequisite for loss of rDNA transcription during cellular
differentiation. We will examine if the loss of UBF during differentiation
also leads to a decreased number of active genes. We will determine
whether enforced expression of UBF can delay or block the down
regulation of rDNA transcription and differentiation. We will look at
the consequences of manipulating UBF levels and number of active
genes during development, in genetic mouse models of cancer and in
embryonic stem cells.
This project will use mouse embryonic stems (ES) cells to explore the
biological function of rRNA gene silencing by manipulating levels of
the Pol I transcription factor UBF and levels of the methyltransferase
DNMT1.
Supervisors: Dr. Elaine Sanij, Dr. Gretchen Poortinga and Assoc. Prof
Ross Hannan
For more information about this project contact: Assoc. Prof. Ross
Hannan, Tel: +61 3 9656 1747, Email: [email protected]; Dr.
Nadine Hein, Tel: +61 3 9656 1806, Email: [email protected]
RNA POLYMERASE I INHIBITORS AS THERAPEUITICS FOR
CANCER: TESTING COMBINATION THERAPIES FOR HEAMTOLOGIC
MALIGNANCIES
Supervisors: Assoc. Prof. Ross Hannan, Dr. Nadine Hein, Dr. Gretchen
Poortinga
Dysregulation of Pol I transcription of the rRNA genes is an almost
universal feature of cell transformation and cancer, and work from
our laboratory has shown that targeting this process is a promising
new approach for cancer therapy. We have shown recently used the
small molecule inhibitor of Pol-1 transcription CX-5461 to selectively
kill B-lymphoma cells in a genetic model of spontaneous lymphoma
while maintaining a viable wild type B-cell population. The therapeutic
effect is a direct consequence of rapid activation of p53-dependent
apoptotic signaling (Bywater et al., Cancer Cell 2012). We are currently
commencing the first clinical trial in humans with CX-5461 to treat
patients with heamatologic malignancies.
This project will test if we can increase the therapeutic potential of Pol I
inhibitors, we will test CX-5461 in combination with standard therapies
(eg. cytarabine and/or anthracylines for AML). As CX-5461 induces
tumour-specific activation of ATM/CHK2 independent of p53, we will
test whether the combination of CX-5461 and CHK2 inhibitors can
induce death of p53 null tumour cells via mitotic catastrophe. As we
hypothesise that MYC expression predicts sensitivity to CX-5461 we
will also test combination therapies with BRD4 inhibitors and PIM kinase
inhibitors both of which have been shown to inhibit MYC expression
and reduce MYC dependence in.
For more information about this project contact: Assoc. Prof. Ross
Hannan, Tel: +61 3 9656 1747, Email: [email protected];
Dr. Nadine Hein, Tel: +61 3 9656 1806, Email: nadine.hein@petermac.
org; Dr. Gretchen Poortinga, Tel: +61 3 9656 1279, Email: gretchen.
[email protected]
Page 8
For more information about this project contact: Assoc. Prof. Ross
Hannan, Tel: +61 3 9656 1747, Email: [email protected]; Dr.
Elaine Sanij, Tel: +61 3 9656 3758, Email: [email protected]
A NOVEL ROLE FOR THE POL I TRANSCRIPTION FACTOR UBF IN
THE REGULATION OF EXPRESSION OF HISTONE GENE CLUSTERS
AND CELLULAR DNA DAMAGE RESPONSES
Transcription of the 200 copies of ribosomal RNA (rRNA) genes by RNA
Polymerase I (Pol I) is one of the most energy consuming processes
and its dysregulation is a consistent feature of cancer. One of the most
important ongoing questions is understanding how Pol I is coupled to
distinct Pol II transcription programs in normal and tumour cells.
We have recently identified novel roles for the Pol I chromatin
remodelling factor UBF. We demonstrated using chromatin
immunoprecipitation (ChIP) sequencing that UBF is enriched at 1700
genes. Analysis of the genes bound by UBF and are differentially
expressed following UBF knockdown suggests that UBF regulates
genes associated with chromatin assembly including histone genes. In
silico Motif analysis suggest that the oncogene c-MYC may cooperate
with UBF to regulate histone gene expression. This project aims to
explore this hypothesis by performing ChIP assays to confirm that
c-MYC is bound at the sites of UBF enrichment in histone genes.
Further, this project aims to examine a model of spontaneous MYC
driven lymphomas (Eμ-Myc) in which MYC is overexpressed in
lymphocytes to explore the dependencies between UBF regulation of
histone gene expression and tumour progression.
For more information about this project contact: Assoc. Prof. Ross
Hannan, Tel: +61 3 9656 1747, Email: [email protected];
Dr. Elaine Sanij, Tel: +61 3 9656 3758, Email: elaine.sanij@petermac.
org; Dr. Gretchen Poortinga, Tel: +61 3 9656 1279, Email: gretchen.
[email protected]
RNA POLYMERASE I INHIBITORS AS THERAPEUITICS FOR
CANCER: ANALYSIS OF p53 -DEPENDENT AND – INDEPENDENT
CELL CYCLE CHECKPOINTS
Supervisors: Assoc. Prof. Ross Hannan, Dr. Nadine Hein and Dr. Elaine
Sanij
The transcription of the 45S ribosomal RNA (rRNA) genes by RNA
Polymerase I (Pol I) is a major rate limiting step for ribosomal biogenesis,
and consequently for cell growth and proliferation. Dysregulation of
Pol I transcription of the rRNA genes is an almost universal feature
of cell transformation and cancer, and work from our laboratory has
shown that targeting this process is a promising new approach for
cancer therapy. We have shown recently used the small molecule
inhibitor of Pol-1 transcription CX-5461 to selectively kill B-lymphoma
cells in a genetic model of spontaneous lymphoma while maintaining
a viable wild type B-cell population. The therapeutic effect is a direct
consequence of rapid activation of p53-dependent apoptotic signaling
(Bywater et al., Cancer Cell 2012). We are currently commencing
the first clinical trial in humans with CX-5461 to treat patients with
heamatologic malignancies.
2014 Peter Mac Student Projects
In addition, we have recently identified a novel p53-independent cell
cycle checkpoint in response to inhibition of Pol I transcription in human
primary fibroblasts, which display a proliferation defect arising from both
G1 and G2 cell cycle arrest. These phenotypes are associated with a
DNA damage – like response.
This project aims to identify the key mechanisms by which cells respond
to acute inhibition of Pol I transcription, which will enable us to predict
which malignancies will respond to this novel treatment strategy.
For more information about this project contact: Assoc. Prof. Ross
Hannan, Tel: +61 3 9656 1747, Email: [email protected]; Dr.
Nadine Hein, Tel: +61 3 9656 1806, Email: [email protected];
Dr. Elaine Sanij, Tel: +61 3 9656 3758, Email: [email protected]
DROSOPHILA MODELS FOR LEUKAEMIA
Supervisors: Dr Leonie Quinn, Assoc. Prof. Ross Hannan
Ribosomal proteins (Rps) are essential for functional ribosomes, protein
synthesis, and proliferative cell growth. Paradoxically, mutation of Rps
can actually promote growth and proliferation and in some cases
bestow predisposition to cancer. Our work provided the first rationale
to explain the counter-intuitive organ overgrowth phenotypes observed
for Drosophila Rp mutants by revealing that Rp mutants can drive tissue
overgrowth cell extrinsically, whereby reduced Rps in the hormonesecreting gland of the larvae decreases activity of the steroid hormone
ecdysone, extending the growth phase of development and causing
tissue overgrowth (Lin et al., PLoS Genetics 2011).
This project aims to extend these studies to better understand how Rp
mutations cause the hypoplastic anemia associated with the human
leukemia. Thus we have developed Drosophila models to specifically
reduce Rps in the hematopoietic system to gain novel insights into
how Rp mutations can promote leukemia (see lymph gland overgrowth
above) in humans. Thus we will gain further insights into the processes
linking reduced levels of Rps to over proliferation of the hematopoietic
system and predisposition to cancer.
For more information about this project contact: Assoc. Prof. Ross
Hannan, Tel: +61 3 9656 1747, Email: [email protected]; Dr.
Leonie Quinn, Email: [email protected]
ASSESSING THE LINK BETWEEN PHENOTYPE SWITCHING AND
DRUG RESISTANCE TO MAPK TARGETED THERAPEUTICS IN BRAF
MUTANT CANCERS
Supervisors: Dr Petranel Ferrao, Dr Amardeep Dhillon
Vemurafenib (Zelboraf®, previously PLX4032) has been approved for
treatment of metastatic melanoma expressing mutant BRAF V600E and
other BRAF targeted therapeutics are under clinical evaluation for other
BRAF mutant cancers. Dramatic responses are observed in over 60%
of melanoma patients, but unfortunately the majority of patients acquire
specific resistance to the drug within a year.
Using various approaches we have determined that drug adaptation
and cell survival is associated with phenotypic switching. It isn’t yet clear
how this altered phenotype contributes to drug resistance in mutant
BRAF V600E cancers.
This project will assess the link between drug adaptation and changes
in cell phenotype. Established models will be utilized to assess the
functional characteristics of cancer cells governed by these phenotypic
changes including proliferation, invasion and migration in vitro, as well
as metastases in vivo. The role of specific transcription factors known
to be regulators of this process will also be determined.
The results of this research project will determine whether phenotype
switching contributes directly to drug resistance and/or progression
of disease, and whether targeting certain modulators to achieve
phenotype reversal may be a beneficial therapeutic strategy.
For more information about this project contact: Dr Petranel Ferrao, Tel:
+61 3 9656 1806, Email: [email protected]; Dr Amardeep
Dhillon, Tel: +61 3 9656 1279, Email: [email protected]
OVERCOMING CHEMORESISTANCE IN AML WITH CHK INHIBITORS
Supervisors: Dr Petranel Ferrao, Prof. Grant McArthur
Several specific inhibitors of the cell cycle checkpoint kinase Chk1 are
currently in clinical development. Some subtypes of AML are inherently
resistant to conventional chemotherapeutics. Our recent studies have
demonstrated that Chk inhibitors are effective in sensitizing these
subtypes of AML to cytotoxic agents.
Page 9
The project will utilize various human AML lines and a murine model
of AML to assess and compare the efficacy of various combinations
of CHK inhibitors with cytotoxics or other targeted therapies. The
results from this project could reveal the underlying mechanisms of
chemoresistance in some subtypes of AML, and will determine the
potential of utilizing selective targeted therapeutics to achieve better
treatment responses in patients.
For more information about this project contact: Dr Petranel Ferrao, Tel:
+61 3 9656 1806, Email: [email protected]; Prof. Grant
McArthur, Tel: +61 3 9656 1954, Email: [email protected]
COMPARING THE EFFICACY OF VARIOUS BRAF AND MEK
TARGETED THERAPUTICS IN BRAF MUTANT THYROID CANCERS
Supervisors: Dr Petranel Ferrao, Prof. Grant McArthur
Vemurafenib (Zelboraf®, previously PLX4032) has been approved for
treatment of metastatic melanoma expressing mutant BRAF V600E.
Dramatic responses are consistently observed in over 60% of BRAFmutant melanoma patients, but unfortunately BRAF-mutant colorectal
patients do not display the same responses. Currently there are several
other BRAF and MEK targeted therapeutics in clinical evaluation.
Although thyroid cancers are rare, they commonly carry the BRAF
V600E mutation. At this stage it is unknown whether thyroid cancer
patients would respond to MAPK targeted therapeutics. Due to a large
panel of currently available therapeutics, it would be beneficial to assess
and compare the available drugs in pre-clinical models.
This project will assess a number of various BRAF and MEK inhibitor
drugs across a panel of BRAF mutant thyroid cell lines. The signaling
and feedback responses in the BRAF-mutant thyroid cell lines will also
be compared to responses in representative BRAF-mutant melanoma,
colorectal and lung cancer cell lines to determine tumour type
differences and similarities.
This project will reveal the best MAPK pathway targeted therapeutic
strategy for clinical evaluation in patients with BRAF-mutant thyroid
cancer.
For more information about this project contact: Dr Petranel Ferrao, Tel:
+61 3 9656 1806, Email: [email protected]; Prof. Grant
McArthur, Tel: +61 3 9656 1954, Email: [email protected]
INHIBITING rDNA TRANSCRIPTION IN MELANOMA
Supervisors: Dr. Karen Sheppard, Assoc. Prof. Ross Hannan and Prof.
Grant McArthur
Increased transcription of ribosomal RNA genes (rDNA) by RNA
Polymerase I is a common feature of human cancer. Recently we
demonstrated that inhibition of rDNA transcription with a small molecule
CX-5461, was effective at reducing rDNA transcription in human
leukemia and lymphoma cell lines and this effect was dependent on
p53 mutational status. Furthermore, in vivo CX-5461 specifically killed
B-lymphoma cells while leaving a viable wild-type B cell population.
These results identify selective inhibition of rDNA transcription as
a therapeutic strategy for cancer specific activation of p53 and
treatment of hematologic malignancies. We will extend these studies
to determine if inhibiting rDNA transcription with CX-5461 is a novel
therapeutic for the treatment of melanoma. To address this we have
assembled an extensive panel of melanoma cell lines, established their
p53 mutational status and performed gene expression profiles of these
cells. Fundamental questions we will address include:
(1) Are melanoma cell lines sensitive to CX-5461 and is this p53
dependent?
(2) Does CX-5461 effectively inhibit rDNA transcription in CX-5461
and resistant cells?
CANCER GENOMICS & GENETICS RESEARCH PROGRAM
EVALUATION OF A CDK4 INHIBITOR IN MELANOMA
Supervisors: Dr. Karen Sheppard, Prof. Grant McArthur
CDK4 and CDK6 are serine/threonine kinases that are central regulators
of the G1-S transition of the cell cycle and are dysregulated in most
cancers including melanoma. In a recent screen of a melanoma cell
line panel we discovered that a small molecule inhibitor of CDK4 was
very effective at inhibiting cell proliferation, suggesting that this may be a
novel treatment for this disease.
Preliminary data indicates that CDK4 inhibitor treatment of cells, in
addition to decreasing cell proliferation, causes a senescent response
that is reliant on the tumour suppressor p53. This project aims to further
explore the mechanism by which the CDK4 inhibitor modulates cell
proliferation, death and senescence in melanoma cells. This will also
incorporate, via genetic manipulation, evaluating the role of p53 in the
CDK4 inhibitor mediated response.
http://www.petermac.org/research/conducting-research/cancer-genomics
Laboratory Heads: Prof. David Bowtell Prof. Ian Campbell, Assoc. Prof. Wayne Phillips, Assoc. Prof. David Thomas
The Cancer Genomics and Genetics program (CGG) seeks to use sophisticated high throughput genomic technologies to improve
our understanding of the biology of cancer and to progress the clinical management of cancer patients through the development
of individualized approaches to treatment. Research in the program focuses primarily on breast, upper gastrointestinal and ovarian
cancers and sarcoma, and involves some of the largest familial and population-based cancer cohorts in the world. These studies
address questions of general importance to solid cancers, including inherited susceptibility to cancer and genome-wide changes
in gene expression, as well as more specific questions such as prediction of response to therapy and the use of gene expression
profiling for accurate cancer diagnosis.
The student will gain experience in many techniques including cell
culture, Western blot, FACS, qRT-PCR, senescence assays and genetic
manipulation via viral transduction.
CANCER GENETICS AND GENOMICS
For more information about this project contact: Dr. Karen Sheppard,
Tel: +61 3 9656 3758, Email: [email protected]; Prof.
Grant McArthur, Tel: +61 3 9656 1954, Email: grant.mcarthur@
petermac.org
Supervisors: Prof. David Bowtell, Dr Dariush Etemadmoghadam
IDENTIFICATION OF NOVEL TREATMENTS FOR OVARIAN CANCER
USING PHARMACO-GENOMIC AND FUNCTIONAL GENOMIC
APPROACHES
Supervisors: Dr. Karen Sheppard, Assoc. Prof. Rick Pearson and
Assoc. Prof. Ross Hannan
Ovarian cancer (OVCA) is the major cause of death from gynecological
malignancy with low survival rates (~30%) being primarily due to drug
resistance. Thus, the identification and validation of new therapeutic
targets is critical for improving patient outcome.
Recent genomic and biochemical analysis of OVCA have identified
a subset of pathway disruptions that provide potential therapeutic
options for this disease; these include retinoblastoma/Cyclin E (67%)
and PI3K/RAS (47%) pathways, and the c-MYC oncogene (20%). It
is now clear that OVCA is a diverse disease that will require individual
characterization of genetic changes to appropriately select treatment
approaches for patients. Thus, our goal is to assess the efficacy of
targeting these dysregulated pathways individually and in combination
to identify new therapeutic approaches to improving patient outcome.
The Project Aims:
(1) To define the contribution of specific pathways dysregulated in
primary tumours to OVCA cell growth and survival and define genomic
biomarkers/signatures associated with response to pathway inhibitors.
(2) To undertake functional analysis of the key pathways implicated in
resistance to standard and targeted therapies and test the efficacy of
rationally designed combination therapies in OvCa cell lines and animal
models
(3) To identify novel targets to improve responses to standard and
targeted therapies using a functional genome-wide RNAi screen.
For more information about this project contact: Dr. Karen Sheppard,
Tel: +61 3 9656 3758, Email: [email protected]; Assoc.
Prof. Rick Pearson, Tel: +61 3 9656 1247, Email: rick.pearson@
petermac.org; Assoc. Prof. Ross Hannan, Tel: +61 3 9656 1747,
Email: [email protected]
MOLECULAR ANALYSIS OF PLATINUM RESISTANCE IN OVARIAN
CANCER
Ovarian cancer is the 5th most common cancer in women, and most
lethal gynaecologic malignancy. Despite aggressive surgery and
platinum-based chemotherapy, the majority of women experience
recurrence and ~70% will succumb to the disease. Resistance to
chemotherapy, or platinum resistance, is the major barrier to long-term
remissions, however the underlying molecular mechanisms are poorly
understood.
We are part of the Australian Ovarian Cancer Study (AOCS), one of
the largest ovarian cancer cohort studies in the world. We are also one
of the two Australian projects funded through a $27 million NHMRC
grant to participate in the International Cancer Genomics Consortium
(ICGC). The ICGC has been established to generate a comprehensive
catalogue of genomic abnormalities, including somatic mutations,
alterations in gene expression and epigenetic modifications, from 50
different cancer types to improve our understanding of the causes of
cancer and identify new methods for treatment and prevention.
Our laboratory is performing whole genome sequencing, RNA-Seq and
methylation arrays on 100 high grade serous cancer samples. These
samples have been carefully selected based on the patients’ response
to platinum based chemotherapy and will provide insights into the
genetic and epigenetic events leading to platinum resistance. Molecular
and functional exploration into mechanisms of platinum resistance in
ovarian cancer will form the basis of the project.
The student will learn key molecular biological techniques and will be
exposed to large-scale human genetic studies that are making use of
the emerging technologies, including microarrays and next generation
sequencing. The Bowtell lab has a very strong reputation in cancer
genetics and genomics, and in fundamental studies in cancer cell
biology. He/she will have the opportunity to contribute insights into one
of the most clinically significant questions in ovarian cancer, platinum
resistance.
For more information about this project contact: Prof. David Bowtell,
Tel: +61 3 9656 1356, E-mail: [email protected]
VALIDATION OF CANDIDATE GENES INVOLVED IN THE
PROGRESSION OF GASTRIC CANCER
Supervisors: Assoc Prof Alex Boussioutas, Dr. Rita Busuttil
This study will utilize many techniques including cell culture, qRT-PCR,
FACS, western analysis and assays to determine cell proliferation rates.
Bioinformatic analysis of gene expression data coupled with sensitivity
profiles will be used to determine predictors of sensitivity.
Gastric cancer (GC) is the fourth most common cancer globally and in
many western countries is usually only diagnosed at advanced stage
giving patients a 5-year survival rate of less than 20%. GC has distinct
premalignant stages that have significant propensity to progress.
The premalignant cascade consists of easily identifiable histological
stages from chronic atrophic gastritis (ChG), intestinal metaplasia (IM)
and dysplasia. The progression through these stages, particularly IM,
takes years, offering a large window of opportunity to intervene. Not
all patients with IM will progress and selection of patients for high-risk
surveillance would reduce the burden of unnecessary screening, patient
anxiety and improve outcomes due to early detection of disease.
For more information about this project contact: Dr. Karen Sheppard,
Tel: +61 3 9656 3758, Email: [email protected]; Assoc.
Prof. Ross Hannan, Tel: +61 3 9656 1747, Email: ross.hannan@
petermac.org; Prof. Grant McArthur, Tel: +61 3 9656 1954, Email:
[email protected]
Relatively little is known about the key genetic events leading to
IM. Our laboratory is currently in the process of completing the first
comprehensive analysis of IM in the world and seeks to identify
candidate genes involved in the progression of IM to GC that can be
used to reliably predict the progression to GC in humans by using
(3) Does CX-5461 induce cell cycle arrest and/or cell death in these
cells and is this p53 dependent?
(4) Are there other predictors of CX-5461 sensitivity?
2014 Peter Mac Student Projects
Page 10
2014 Peter Mac Student Projects
a genomics based approach. Identification of such genes offers an
opportunity to study the molecular mechanisms involved and pinpoint
targets for prevention and therapy. The aim of this project is validate
these candidate genes using an independent data set and then
characterizing these genes using functional assays and animal models.
We are looking for motivated students (both Honours and PhD
students) to strengthen our group. The project will use broad range
techniques including bioinformatics, cell culture, animal models and
molecular biology.
For more information about this project contact: Assoc. Prof. Alex
Boussioutas, Tel: +61 3 9656 1287, Email: alex.boussioutas@
petermac.org; Dr. Rita Busuttil, Tel: +61 3 9656 1287, Email: rita.
[email protected]
ROLE OF THE TUMOUR MICROENVIRONMENT IN GASTRIC
CANCER
Supervisors: Assoc. Prof. Alex Boussioutas, Dr. Rita Busuttil
Gastric cancer (GC) is the fourth most common cancer globally and
7th in incidence in Australia. It has a poor survival rate which can be
attributed to the advanced stage at diagnosis in most patients. The
molecular and cellular mechanisms underlying the development of GC
are not well described.
Traditionally cancer research involved studying the cancer cell itself.
More recently, there has been growing interest in studying the normal
cells and molecules which surround the cancer cell. This tumour
microenvironment consists of a variety of stromal cell types including
cells such as fibroblasts. It is believed that the dynamic communication
between tumour cells and the surrounding cell types may play a major
role in cancer initiation, progression and establishment of metastatic
disease. The aim of this project is to investigate tumour-stromal
interactions in gastric cancer utilizing established and primary cell lines.
Once the molecular pathways by which a tumour cell progresses has
been elucidated it is possible that these processes could be exploited in
the development of novel therapeutics.
This project will use a broad range of techniques such as live cell
microscopy, cell culture techniques and siRNA to interrogate the
function of gene products that influence tumour-stroma communication.
Our previous genomic experiments have provided us with a number of
exciting candidate genes that may be involved in this interaction. This
is novel research that may have a major benefit to our understanding of
cancer and improve patient outcomes.
For more information about this project contact: Assoc. Prof. Alex
Boussioutas, Tel: +61 3 9656 1287, Email: alex.boussioutas@
petermac.org; Dr. Rita Busuttil, Tel: +61 3 9656 1287, Email: rita.
[email protected]
TWIST AS A REGULATOR OF EMT IN GASTRIC CANCER AND ITS
ROLE IN INVASION
Supervisors: Assoc Prof Alex Boussioutas, Dr. Rita Busuttil
Gastric cancer (GC) is often diagnosed at advanced stages, giving
patients a 5-year survival of less than 20%. Advanced stage GC is
directly correlated with increased local invasion of the cancer through
the gastric wall and, at more advanced stages into adjacent structures.
Epithelial Mesenchymal Transition (EMT) is one mechanism which
has been proposed as a modulator of invasion in GC as well as other
cancer types. This project seeks to expand on previous work in our
Page 11
laboratory exploring the role of TWIST, a master regulator of EMT, in
gastric cancer. We have previously shown that TWIST is more highly
expressed at the invasive front of the tumor compared to its core
indicating that EMT is occurring in this area. It is conceivable that
reducing TWIST expression could be used as a means to decrease the
invasive capacity of a cancer.
This project will aim to further explore the role of TWIST in the invasion
of GC and its potential utility as a therapeutic target. A broad range
of techniques including bioinformatics, cell culture, shRNA lentivirus
mediated gene knockdown, and molecular biology will be applied.
We are looking for motivated students (both Honours and PhD
students) to strengthen our group.
For more information about this project contact: Assoc. Prof. Alex
Boussioutas, Tel: +61 3 9656 1287, Email: alex.boussioutas@
petermac.org; Dr. Rita Busuttil, Tel: +61 3 9656 1287, Email: rita.
[email protected]
DEVELOPING PERSONALISED TARGETED THERAPIES FOR
OESOPHAGEAL CANCER
IDENTIFICATION OF HIGHLY PENETRANT GENES IN FAMILIAL
BREAST CANCER USING NEXT-GENERATION SEQUENCING
Supervisors: Dr Nicholas Clemons, Assoc. Prof. Wayne Phillips
Supervisors: Assoc. Prof. Ian Campbell, Dr. Ella Thompson and Dr.
Alison Trainer
The incidence of oesophageal adenocarcinoma (OAC) is rising
faster than any other cancer and patients with OAC have very poor
outcomes. There are few treatments for OAC, and many patients do
not respond to the chemotherapy commonly given as part of standard
treatment to those with “curable” disease. Therefore, there is an urgent
need to develop new treatments for OAC. However, progress has
been hindered by a lack of appropriate pre-clinical models. We have
developed a novel patient derived tumour xenograft (PDTX) model
for OAC in which tumour pieces from patients are implanted and
grown in mice. This aim of this project will be to utilize this model to
evaluate novel therapies for OAC by identifying and testing appropriate
molecularly targeted therapies and biomarkers that predict therapeutic
response that can then be applied on an individual basis to patients.
SURGICAL ONCOLOGY
For more information about this project contact: Dr Nicholas Clemons,
Tel: +61 3 9656 1849; Email: [email protected]
IN VITRO STUDIES ON THE MECHANISM OF ACTION OF PIK3CA
MUTATIONS IN BREAST CANCER
THE INTERACTION OF P53 AND PIK3CA MUTATIONS IN BREAST
CANCER
Supervisor: Assoc. Prof. Wayne Phillips
Supervisors: Assoc. Prof. Wayne Phillips, Dr. Sue Haupt, Prof. Ygal
Haupt
The phosphoinositide 3-kinase (PI3K)/Akt signalling pathway controls
a range of fundamental cellular processes which, when de-regulated,
are considered hallmarks of cancer. It is now well established that
somatic mutations in PIK3CA, the gene coding for the p110α catalytic
subunit of PI3K, are one of the most common, and thus potentially
one of the most important, genetic abnormalities in many human
tumours including breast cancer. However, it remains unclear how these
mutations drive tumourigenesis.
We have recently generated a novel mutant mouse with which to
study the role of the common tumour-associated PI3K mutation,
PIK3CAH1047R. Our strategy of making the mutation inducible allows
us to target the expression of the mutant to specific tissues. We can
also induce the expression of the mutation in cells growing in culture
allowing us to examine the effects of PIK3CAH1047R mutation in vitro
under defined conditions.
The student will isolate and culture mammary epithelial cells from
our PIK3CAH1047R mouse and use these to examine the signalling
pathways by which PIK3CAH1047R induces tumourigenesis
and regulates the growth and differentiation of mammary
epithelial cells. Techniques to be used will include tissue culture,
immunohistochemistry, immunofluorescence, confocal microscopy
and western blotting, as well as in vitro and in vivo assays to assess
functional activity such as proliferation, apoptosis, and tumourigenesis.
For more information about this project contact: Assoc. Prof. Wayne
Phillips, Tel: +61 3 9656 1842; Email: [email protected].
USING HIGH-THROUGHPUT FUNCTIONAL GENOMICS SCREENS
TO IDENTIFY GENES AND PATHWAYS THAT COOPERATE WITH
PIK3CA MUTATIONS
Supervisor: Assoc. Prof. Wayne Phillips
Mutations in the PI3K pathway are one of the most important genetic
abnormalities in human cancer. Thus, the clinical development of
PI3K pathway inhibitors is currently one of the most active oncologyrelated endeavours within the pharmaceutical industry. Early human
clinical trials have been disappointing in that PI3K inhibition appears
to induce tumour stasis at best indicating that combination therapies
will be essential. However, candidate-based approaches to identifying
combination therapies have met with limited success and there is
now a critical need for innovative new targets for developing the next
generation of anti-cancer therapeutics.
In this project the student will undertake high-throughput, in vivo,
functional genomics screens in our unique mouse model to identify
novel pathways that functionally cooperate with Pik3ca mutation
to initiate tumourigenesis in the mammary gland. They will use a
genome-wide shRNA library and/or the ‘Sleeping Beauty’ transposon
mutagenesis system to conduct unbiased forward genetic screens in
vivo to identify novel genes and pathways that cooperate with Pik3ca
mutation to induce mammary tumourigenesis. They will then go on use
in vitro and in vivo model systems to confirm and validate the functional
interactions identified and explore their potential as novel therapeutic
targets.
The p53 tumour suppressor gene and the phosphoinositide 3-kinase
(PI3K)/Akt signalling pathways both independently control a range
of fundamental cellular processes which, when de-regulated, are
considered hallmarks of cancer. We have recently used a novel mutant
mouse to study the in vivo interaction of these two pathways in breast
cancer and demonstrated a significant synergy between p53 and
Pik3ca mutations in the induction of breast cancer. The student will
use this mouse model to further explore the interaction of p53 and
Pik3ca. This will involve both in vivo mouse work and also in vitro
studies on cultured mammary epithelial cells. The student will examine
the signalling pathways by which p53 and pik3ca interact to regulate
the growth and differentiation of mammary epithelial cells and induce
tumourigenesis. Techniques to be used will include tissue culture,
immunohistochemistry, immunofluorescence, confocal microscopy,
and western blotting, as well as in vitro and in vivo assays to assess
functional activity such as proliferation, apoptosis, and tumourigenesis.
For more information about this project contact: Assoc. Prof. Wayne
Phillips, Tel: +61 3 9656 1842; Email: [email protected];
Prof. Ygal Haupt, Tel: +61 3 9656 5871; Email: ygal.haupt@petermac.
org; Dr. Sue Haupt, Email: [email protected]
VBCRC CANCER GENETICS
IMPROVING OUTCOMES FOR WOMEN DIAGNOSED WITH
MUCINOUS OVARIAN CANCER
Supervisors: Prof. Ian Campbell, Dr. Kylie Gorringe
Mucinous ovarian carcinoma (MOC) differs in appearance and behavior
from the other common epithelial ovarian cancer subtypes. MOC
is frequently confused with metastases from organs such as the
appendix, but it is not known if this resemblance extends to similarities
in genetic alterations. Advanced MOC does not respond well to
conventional ovarian cancer chemotherapies, indicating that there
is a need for more subtype-specific therapies. We hypothesise that
genomic aberrations found in MOC will be similar to those in mucinous
cancers from other organs. Consequently, MOC may be better treated
with chemotherapeutics that show success with other mucinous
tumours.
This project will obtain genomic data from primary MOC and compare
this with data from metastases to the ovary from extra-ovarian sites
(initially presenting as ovarian), appendiceal tumours, gastric tumours,
mucinous colorectal tumours and pancreatic tumours. Techniques
used will include copy number arrays and next-generation sequencing
(exome and RNAseq). This NHMRC-funded project is an exciting
opportunity to collaborate with clinical and research staff at WEHI and
Royal Melbourne Hospital with a high likelihood of changing clinical
practice and improving health outcomes for women.
For more information about this project contact:
Prof. Ian Campbell, Tel +61 3 9656 1803 Email: ian.campbell@
petermac.org; Dr Kylie Gorringe, Tel +61 3 9656 1131 Email: kylie.
[email protected]
For more information about this project contact: Assoc. Prof. Wayne
Phillips, Tel: +61 3 9656 1842; Email: [email protected].
2014 Peter Mac Student Projects
Page 12
The ability to identify disease-causing mutations in high-risk cancer
families has broad implications for those affected in terms of risk
assessment and management as well as treatment. A major initiative
over the last year has been the application of next generation
sequencing (NGS) to identify cancer predisposition genes. We are
performing whole exome sequence analysis of germline DNA from
multiple affected relatives from over 75 high risk non-BRCA1/nonBRCA2 breast cancer families with the aim of identifying segregating,
rare, non-synonymous variants that are likely to include novel
predisposing mutations.
This project will perform and analyse NGS data to identify candidate
gene variants identified and validate these variants in the family in which
the variant was found including segregation analysis. After validation,
the gene will be further analysed for mutations in other families and
individuals with the same cancer type through boutique exon capture
and NGS. Techniques used will include DNA sequencing (NGS and
Sanger), bioinformatics, PCR, high resolution melting and potentially
assays of gene transcription or function.
For more information about this project contact: Prof. Ian Campbell, Tel
+61 3 9656 1803 Email: [email protected]
UNDERSTANDING THE GENETIC PREDISPOSITION TO MALE
BREAST CANCER USING A WHOLE EXOME SEQUENCING
APPROACH
Supervisors: Prof. Ian Campbell, Dr. Alison Trainer and Dr. Ella
Thompson
Despite a higher mortality rate associated with male breast
cancer (MBC) compared to its female counterpart, MBC is still
disproportionately underrepresented in all forms of breast cancer
research. MBC show a significant overlap with FBC in terms of
epidemiology, morphology and inheritance patterns, yet the majority
of families with a familial male breast cancer risk are not attributable to
BRCA1/2 mutations and are of unknown aetiology.
This project brings together familial cancer clinics across Australia to
form a national cohort of familial MBC cases with well- described clinical
data and links directly to other ongoing breast cancer genomic studies
within the group.
The successful candidate on this project will join a well–established
genomics research group and use whole exome capture and next
generation sequencing technology to identify novel causative genes
underlying the predisposition to male breast cancer.
Significantly, as male breast cancers are overwhelmingly oestrogen
receptor positive, completion of this project should not only identify
genes predisposing to MBC but also has the potential to provide
genetic and biological insight into the large proportion of sporadic FBC,
which are also oestrogen receptor positive on histopathology
For more information about this project contact: Dr. Alison Trainer, Tel
+61 468575700 Email: [email protected]
COMBINATORIAL GENE KNOCKDOWN FOR FUNCTIONAL
CHARACTERISATION OF GENE AMPLICONS IN OVARIAN CANCER
Supervisors: Dr Kylie Gorringe, Dr Kaylene Simpson, Prof Ian Campbell
Current treatment for ovarian cancer includes surgery and
chemotherapy, but therapy resistance is common. High-grade
carcinomas with high-level copy number amplification of 19q have
increased resistance to treatment and reduced survival. These patients
represent an area of particular need for new therapeutic agents. The
discovery of molecular targeted agents towards genes affected by
amplification, such as Herceptin for ERBB2 is a key area of research
with the potential to improve the survival outcomes of patients.
This study will characterise key genes and their interactions within
two common amplification events in ovarian cancer. Our previous
high-throughput siRNA screen identified 5 genes in 2 amplicons on
chromosome 19q that individually invoke strong viability phenotypes
when knocked down. Simultaneous knockdown of these genes may
have a synergistic effect on cell phenotype and the strength of this
effect will have implications for treatment using molecular agents against
the gene products. Such agents are available for two of the genes to
be targeted and will be included in combination with each other and
siRNAs.
2014 Peter Mac Student Projects
This project will involve cell culture, treatment with siRNAs and small
molecule inhibitors utilizing the high-throughput screening robotics
system of the Victorian Centre for Functional Genomics (VCFG), and
downstream assays including assessment of cell viability, RTPCR and
Western blotting.
For more information about this project contact: Prof. Ian Campbell, Tel
+61 3 9656 1803 Email: [email protected]; Dr Kylie Gorringe,
Tel +61 3 9656 1131 Email: [email protected]
SARCOMA GENOMICS & GENETICS
GENETIC AND MOLECULAR MECHANISMS DRIVING THE
EVOLUTION OF DRUG RESISTANCE IN A HUMAN LIPOSARCOMA
CELL LINE
Supervisors: Dr. Arcadi Cipponi, Assoc. Prof. David Thomas
The major cause of cancer therapy failure is either primary drug
resistance in cancer cells, or the development of secondary resistance
mechanisms against chemotherapeutic or molecular targeted drugs.
The phenomenon of drug resistance is seen across a broad spectrum
of cancers and affects most patients. Although the mechanisms leading
to acquisition of drug resistance in tumours have been the subject of
intense study, effective strategies to prevent this phenomenon remain
elusive.
We have established an in vitro model system in which the human welldifferentiated liposarcoma (WDLPS) cell line (778) is used to study the
evolution of resistance to Nutlin-3, a clinically approved small molecule
antagonist of MDM2. Nutlin-3 inhibits the p53-MDM2 interaction, and
activates p53-dependent pro-apoptotic pathways in cancer cells. The
main goals of the project are to investigate the (epi)genetic factors
and the molecular pathways that contribute to the development of
resistance to Nutlin-3. Preliminary results obtained analysing the gene
expression profile associated with drug resistance show a reduction of
the expression of genes involved in DNA repair processes, as well as an
increased level of genetic instability revealed by the presence of a higher
number of DNA double strand breaks (DSBs).
We are focusing our studies on both the role of genetic instability and
on functional studies of candidate genes implicated in the acquisition of
drug resistance. The results may provide clinically relevant insights into
the acquisition of drug resistance in tumours, paving a way to identify
genes and/or molecular pathways that could be targeted to prevent
tumours from developing drug resistance in the clinic.
For more information about this project contact: Dr. Arcadi Cipponi, Tel:
+61 432 474437; Email: [email protected]; Assoc. Prof.
David Thomas. Tel +61 3 9656 1238 Email david.thomas@petermac.
org
ROLE OF IMMUNOMODULATORS IN THE IN VIVO DEVELOPMENT &
PROGRESSION OF OSTEOSARCOMA
Supervisors: Assoc. Prof. David Thomas, Dr. Maya Kansara
The Sarcoma Genetics and Genomics laboratory studies tumours of
soft tissue and bone. Osteosarcoma is the most common cancer
of bone. These tumours are highly metastatic and often metastasise
to lung via the hematogenous route. Treatment involves aggressive
surgery with intensive adjuvant chemotherapy. Although these
measures have improved prognosis, a third of those diagnosed will
die from this disease. Understanding how osteosarcoma arises and
persists will enable the development of targeted therapies. The skeleton
and the immune system share a number of cytokines and transcription
factors and therefore may mutually influence each other; the study of
these cells and their interactions has been termed osteoimmunology.
In this project we will investigate the interaction between the immune
system and bone cancer in an in vivo mouse model of osteosarcoma.
The project will use broad range techniques including mouse models of
cancer, histology, cell culture, flow cytometry, and molecular profiling.
For more information about this project contact: Assoc. Prof. David
Thomas. Tel +61 3 9656 1238 Email: [email protected]; Dr.
Maya Kansara Tel +61 3 9656 1618 Email: maya.kansara@petermac.
org
Page 13
MOLECULAR BIOMARKERS AND TRANSLATIONAL
GENOMICS
Supervisor: Dr Sarah-Jane Dawson
Overview: The molecular biomarkers and translational genomics
laboratory aims to develop improved biological markers for early cancer
detection, risk stratification and disease monitoring. Our group will
apply cutting-edge molecular approaches in translational studies to
study and develop novel biomarkers for clinical application.
Advances in next-generation sequencing technologies are currently
leading to an expansion of our knowledge of the genetic mechanisms
underpinning various cancers. Our laboratory is focussed on
the integration of this knowledge into the clinical arena and the
development of personalised biomarkers to improve clinical care and
patient outcomes.
The use of circulating tumour DNA (ctDNA) as a non-invasive molecular
biomarker represents a key advance in this area. Cell-free circulating
DNA containing tumour-specific sequences can be identified in the
plasma of cancer patients. Serial analysis of ctDNA can allow the
evolving genomic landscape of a cancer to be assessed, with many
potential clinical applications including the early detection of disease
recurrence, the assessment of prognosis and the monitoring of
response to treatment. Analysis of ctDNA is challenging and requires
highly sensitive techniques due to the small fraction of tumour specific
DNA present in the circulation amidst background levels of DNA
from healthy cells. The application of next-generation sequencing
technologies is now providing new opportunities to develop ctDNA as
a non-invasive ‘liquid biopsy’ alternative to tissue biopsies for use in
cancer diagnostics and management.
Broad research aims:
• The application of next-generation sequencing technologies to study
tumour-specific genomic alterations, and guide diagnostic, prognostic
and therapeutic decisions in the clinic.
• The use of non-invasive molecular biomarkers (such as circulating
tumour DNA and circulating tumour cells), to study disease progression,
tumour evolution and therapeutic resistance in cancer.
BIOINFORMATICS AND COMPUTATIONAL GENOMICS
IDENTIFYING INTRA-TUMOURAL HETEROGENEITY IN CANCER –
OMICS DATA
Supervisors: Dr Tony Papenfuss, Dr Mark Shackleton
Bioinformatics is the application of mathematics, statistics and
computational methods to the analysis of -omics data. Our research
is focused on developing new bioinformatics methods and applying
new and existing methods to analyze and make sense of complex
cancer datasets. Much of our efforts are focused on next generation
sequencing data and we have particular interest in methods to analyze
structural variation, heterogeneity and evolution in cancer.
There is a growing awareness of the importance of intra-tumour
heterogeneity (ITH) in determining outcomes of cancer patients. The
ideal data for assessing ITH is likely to be derived from multiregional
sampling of tumours, but this is difficult to attain. Another approach
is to examine single tumor samples for signs of heterogeneity. A
few bioinformatics methods exist to do this, but there remain many
challenges. This project will involve understanding existing approaches
and developing and applying new methods to identify ITH and to
evaluate its relationship to and effect on cancer biology outcomes,
including patient survival and therapy response.
Project references:
1. Carter et al., Absolute quantification of somatic DNA alterations in
human cancer, Nat Biotechnol. 2012 May;30(5):413-21
2. Nik-Zainal et al., The life history of 21 breast cancers, Cell. 2012 May
25;149(5):994-1007
3. Oesper et al., THetA: Inferring intra-tumor heterogeneity from highthroughput DNA sequencing data, Genome Biology 2013, 14:R80
For more information about this project contact: Dr Tony Papenfuss,
Email: [email protected] Dr. Mark Shackleton, Tel: +61 3 9656
5235; Email: [email protected]
http://www.petermac.org/research/conducting-research/cancer-therapeutics
Laboratory Heads: Professor Ricky Johnstone, Professor Grant McArthur, Dr Mark Shackkleton, Dr Sherene Loi, Dr Mark Dawson,
Dr Ben Solomon
The Cancer Therapeutics program, together with the Molecular Imaging and Translational Medicine Program, is designed to integrate
various basic research activities, platform technologies, and pre-clinical model systems available within the Peter Mac to discover,
develop, characterise and refine novel cancer therapeutics for clinical use. Basic research within the program is focused on increased
understanding of the biological basis of disease patterns and treatment outcomes observed in the clinic, preclinical testing of novel
therapeutics, development of imaging methods and biomarker assays to follow treatment efficacy and investigation of cellular
pathways involved in response to anticancer therapies.
GENE REGULATION
BASIC AND PRE-CLINICAL RESEARCH AIMED AT DEFINING THE
MOLECULAR PROCESSES REQUIRED FOR ANTI-CANCER DRUG
ACTION AND DRUG RESISTANCE.
Our research focus includes:
• Discovering and analysing epigenetic enzymes important for the
growth and survival of haematological tumours including B- and T-cell
leukaemia and lymphoma, acute myeloid leukemia (AML) and multiple
myeloma (MM).
• Conducting basic and pre-clinical characterisation of novel apoptosisinducing therapeutic agents used alone and in combination.
Cancer is a genomic disease and tumour specific genomic
alterations are increasingly being used to guide the management of
cancer patients. Cancer cells release DNA into the blood and the
measurement of cell-free circulating tumour DNA (ctDNA) offers a
unique opportunity to non-invasively study the evolving genomic
landscape of the underlying tumour. The analysis of ctDNA is
challenging and requires highly sensitive techniques due to the small
fraction of tumour specific DNA present in the circulation amidst high
background levels of DNA from normal cells. The application of next
generation sequencing technologies is now providing new opportunities
to develop ctDNA as a ‘liquid biopsy’ alternative to tissue biopsies
for use in cancer diagnostics and management. Through recent
advances, it is now possible to characterise specific DNA mutations in
a patient’s tumour, design assays to identify these mutations, and then
apply these assays to plasma to accurately measure the amount of
ctDNA. The potential clinical applications of this new technology are
far-reaching (Dawson et al, NEJM, 2013).
• Developing use of genetically engineered mouse models of
haematological malignancies and solid cancers for pre-clinical studies.
Radiotherapy (RT) is effective for local tumor control but against
metastases, arising outside the field of radiation treatment, its curative
capacity is limited, despite the reported ability of RT to stimulate antitumor immune responses. To enhance the systemic effects of RT we
have looked to use this important anti-cancer therapy together with
antibodies designed to promote the tumor-specific immune responses
evoked by the “vaccine-like” effects of radiation-induced cell death.
1. SJ. Dawson et al. (2013) New England Journal of Medicine. 368(13): 1199209.
2. M. Murtaza et al. (2013) Nature. 497(7447): 108-12.
For more information about this project contact: Dr Sarah-Jane Dawson
[Currently based at the Cancer Research UK Cambridge Institute, UK
Ph: +44 1223769747 Email: [email protected]
Page 14
(i) Characterize the mechanisms by which RT can alter the susceptibility
of primary and metastatic tumors to rejection by immune-modulatory
antibodies.
TRACKING CLONAL EVOLUTION IN MURINE CANCERS BY
CELLULAR BARCODING AND MASSIVELY-PARALLEL SEQUENCING
The more we learn about the mechanism(s) of action of RT and its
impact on various immune parameters and tumor microenvironments,
this will ensure that its full therapeutic potential can be harnessed
against metastatic breast cancer. This exciting project area has recently
attracted funding support from the Cancer Council of Victoria and
Susan G Komen.
Genetically engineered mouse models are a powerful research tools
to study cancer evolution. Using massively-parallel sequencing in
combination with mouse cancer models our lab has been able to
catalogue and track mutations arising in spontaneous lymphomas
and leukemias. We have done this by sequencing the genomes of
cancer cells at end stage disease and then by using deep sequencing
3. SJ. Dawson et al. (2013) EMBO Journal. 32(5): 617-28.
This project aims to use preclinical mouse models of breast cancer to:
(ii) Identify the tumor-associated factors that permit and/or restrict the
effectiveness of anti-tumor responses to RT.
The prevailing view of cancer is that neoplastic transformation results
from the acquisition of somatic mutations leading to evasion of the
body’s intrinsic anti-cancer mechanisms. The process by which this
occurs is thought to closely mimic that of species evolution, but in
this instance a tumor cell sequentially acquires a number of mutations
that provides a selective growth advantage to the cell. Evidence for
clonal evolution in cancer has been known for some time, but only
recently with the advent of new technologies like massively-parallel
(next-generation) sequencing have we been able to fully appreciate how
integral this process is to cancer development. Understanding cancer
evolution is important as it provides an insight into early processes of
neoplasia, for example, what genes are implicated in cancer initiation
versus those that are more important later in disease development.
It also has implications for treatment as cancer evolution can result in
acquired resistance to therapy.
References:
Supervisor: Dr Nicole Haynes
For more information about potential projects contact: Prof Ricky
Johnstone, Tel: +61 3 9656 3727; Email: ricky.johnstone@petermac.
org; Dr Geoff Matthews, Tel: +61 3 9656 3724; Email: geoff.
[email protected]; Dr Jake Shortt, Tel: +61 3 9656 3724; Email:
[email protected]; Dr Michaela Waibel, Tel: +61 3 9656 3725;
Email: [email protected]
Supervisors: Dr Richard Tothill and Prof. Ricky Johnstone
This project will utilise ctDNA to study how breast cancers evolve when
they progress and become resistant to treatment. It will evaluate if
ctDNA can be used as a form of ‘liquid biopsy’ to serially follow patients
and individualise treatment decisions in breast cancer. The project
will utilise next generation sequencing techniques, digital PCR and
bioinformatic approaches to quantify ctDNA in clinical samples and
correlate these findings with clinical features. The ultimate aim of this
research is to develop ctDNA as a personalised biomarker to provide
the opportunity for molecular disease monitoring in breast cancer.
For more information about this project contact: Prof Ricky Johnstone,
Tel: +61 3 9656 3727; Email: [email protected]; Dr
Richard Tothill, Tel: +61 3 9656 1752; Email: Richard.tothill@petermac.
org
RADIO-IMMUNOTHERAPY AND BREAST CANCER
Research in the laboratory falls under two major themes: defining the
molecular events underpinning anti-cancer drug action and resistance
and using this information in pre-clinical studies to design and test novel
therapeutics alone and in combination, and dissecting the role of altered
epigenetics in tumour onset and progression, targeting epigenetic
enzymes to treat cancer.
Supervisor: Dr Sarah-Jane Dawson
searched for the same mutations in early stage pre-cancerous cells
taken from the circulating peripheral blood of the animal at time points
during disease progression. Another way to monitor clonal evolution
is to introduce unique cellular DNA barcodes to the genomes of
cells through viral transduction. Using massively-parallel sequencing,
cellular barcodes can be used to monitor clonal expansion in the
absence of known somatic mutations. These methods will be useful
for understanding the mechanism of resistance to drug treatment and
will be integrated with the preclinical testing of novel therapeutic agents
currently underway in the lab.
• Determining the effects of combining novel agents designed to
specifically kill breast cancer cells with other agents that stimulate a host
anti-tumour immune response.
• Functional genomics-based screens to identify novel tumour
suppressor genes and genes that regulate the apoptotic response to
new anti-cancer agents.
CIRCULATING TUMOUR DNA AS A PERSONALISED BIOMARKER IN
BREAST CANCER
2014 Peter Mac Student Projects
CANCER THERAPEUTICS RESEARCH PROGRAM 2014 Peter Mac Student Projects
(iii) Develop new radio-immunotherapy combinations, based on the
findings from the above aims and test their therapeutic activity in
experimental and spontaneous mouse models of breast cancer.
We are looking for a highly motivated PhD or Honours student to take
on this project with an interest in immunology and applied/translational
academic science.
For more information about this project contact: Dr Nicole Haynes, Tel
+61-3-9656 1752, Email: [email protected]
THE THERAPEUTIC EFFICACY AND MECHANISMS OF ANTIBODYBASED THERAPIES IN BREAST CANCER
Antibodies are now considered key therapeutic drugs for the treatment
of cancer. Trastuzumab is one such prototypic antibody designed to
block the growth promoting activity of the breast cancer associated
receptor HER2; expressed on 12-25% of invasive breast cancer. Its
use as a mainstay therapy has seen the risk of breast cancer relapse
decrease by 50% and the rate of death by a third. However, there
are a group of patients that do not respond or develop resistance
to Trastuzumab and thus there remains an unmet medical need for
new antibody-based HER2 targeted combination strategies. Histone
deacetylase inhibitors (HDACi) are a promising class of anti-cancer
Page 15
drugs that have the capacity to promote and/or reengage the
therapeutic activity of Trastuzumab via multiple mechanisms.
This project is aimed at examining the therapeutic efficacy and
mechanisms underpinning the capacity of antibody-based HER2targeted therapies and HDACi to synergistically evoke durable antitumour responses in preclinical mouse models of human and mouse
HER2+ breast cancer.
Identification of the genes and/or immune signatures predictive of
therapeutic outcome will ultimately help with the development of more
personalized treatment strategies for HER2+ breast cancer.
We are looking for a highly motivated Honours student to take on
this project with an interest in immunology and applied/translational
academic science.
For more information about this project contact: Dr Nicole Haynes,
Tel +61-3-9656 1752, Email: [email protected]; Dr Ricky
Johnstone, Tel +61-3-9656 3727, Email: [email protected]
MELANOMA RESEARCH
Melanoma is a common cancer and a source of significant morbidity
and mortality in our community, particularly among 20-40 year-olds
where it is the most common cause of cancer death. As a result,
melanoma causes the second/third most years of lost productive life of
all cancers in males/females. Disturbingly, the incidence of melanoma
is increasing in Australia and deaths attributable to the disease are
projected to increase accordingly. Compounding the increasing disease
and economic burden imposed by melanoma in our community is the
lack of effective therapies for patients with advanced disease.
Our research program seeks to address the problem of melanoma
using two approaches. First, through improving understanding of
normal melanocyte development, we aim to identify mechanisms of
melanomagenesis and thereby develop strategies for improved disease
prevention. Second, through use of a highly efficient model of human
melanoma progression that replicates closely the biology of this disease
in patients, we aim to identify mechanisms of melanoma propagation
and metastasis. Our close links with the clinical research activities of
the Peter Mac Melanoma Unit enable rapid clinical translation of our lab
discoveries in order to help patients.
IDENTIFICATION OF DETERMINANTS OF MELANOMA
PROGRESSION
Supervisors: Dr. Mark Shackleton and Assoc. Prof. Grant McArthur
This project will use a novel human melanoma tumorigenesis assay
(Nature 456:593) to study how melanomas progress once they have
formed. This assay offers a unique opportunity to study human cancer
biology, genetics and epigenetics at the clonal level. By comparing
the malignant and molecular properties of sister clonal tumors, this
approach enables direct correlation of tumor phenotype and genotype/
epigenotype in a way that is likely to reveal those molecular aberrations
that are functionally relevant to malignant progression and potentially
target-able by modern therapeutic approaches. Multiple projects within
this framework are planned, involving a wide range of techniques:
working with fresh human tumor specimens and analyzing clinical data,
mouse handing and surgery, immunostaining and flow cytometry, and
molecular studies such as SNP genotyping, DNA methylation analysis,
NextGen sequencing and functional genomics.
For more information about this project contact: Dr. Mark Shackleton,
Tel: +61 3 9656 5235; Email: [email protected]
THE FUNCTIONAL CONSEQUENCES OF MELANOMA CELL
PIGMENTATION
Supervisors: Dr Mark Shackleton and Dr Clare Fedele
Melanoma is the commonest cancer affecting young Australians and
has a disproportionately high socioeconomic impact in this country.
Unravelling the complex biology of this disease is expected to lead to
improved treatment of patients. Although most melanomas contain
melanin pigment, pigmented melanomas are usually comprised of
heterogeneously pigmented cells. In the context of the stem cell model
of cancer progression, this raises the question of whether differences in
melanin pigment content, which may be a marker of the differentiation
status of melanoma cells, are associated with differences in the
potentials of these cells to propagate disease. Moreover, it is not known
whether the relationships between pigmented and non-pigmented
melanoma cells are hierarchical (and thus consistent with a CSC model)
or plastic. This project will address these questions using melanoma cell
lines, patient-derived melanomas, flow cytometry, cell culture, animal
tumorigenesis studies and molecular profiling.
2014 Peter Mac Student Projects
For more information about this project contact: Dr. Mark Shackleton,
Tel: +61 3 9656 5235; Email: [email protected]; Dr Clare
Fedele, Email: [email protected]
CHARACTERIZATION OF NORMAL MELANOCYTE DEVELOPMENT
Supervisors: Dr. Mark Shackleton, Assoc. Prof. Grant McArthur
This project will adapt classical stem cell biology techniques developed
in other solid organ systems (Nature 439:84) to the study of normal
melanocyte development. Using sophisticated mouse models,
melanocytes at different stages of development will be conditionally
tagged, isolated and functionally characterized. The oncogenic effects
of various genetic and environmental stimuli on melanocyte lineage
subpopulations will then be studied, and strategies explored to prevent
oncogenesis in different contexts. Complementary studies of human
melanocyte development will also be performed. Techniques used will
include working with mouse models, cell culture, flow cytometry and
cell sorting, microarray-based gene expression studies, and qPCR.
For more information about this project contact: Dr. Mark Shackleton,
Tel: +61 3 9656 5235; Email: [email protected]
TRANSLATIONAL BREAST CANCER GENOMICS
The Translational Breast Cancer Genomics Lab focuses on the
translation of scientific findings into treatment approaches for breast
cancer patients. Its main focus is breast cancer biology, mechanisms
of resistance and response to current breast cancer therapies and the
development of novel therapeutic approaches.
CLINICAL RELEVANCE OF CO-EXISTENT MUTATIONS WITH PIK3CA
MUTATIONS IN BREAST CANCER
Supervisor: Dr Sherene Loi
Somatic mutations in PIK3CA, the gene coding for the p110α catalytic
subunit of PI3K, are present in up to 40% of estrogen receptor (ER-)
positive breast cancer. The main stay of such treatment is endocrine
therapy. We have reported that ER-positive breast cancers with a
PIK3CA mutation can have quite good clinical outcomes compared
with their wild-type counterparts. However, we have found in metastatic
breast cancer samples a high frequency of mutations co-existent with
PIK3CA- KRAS, BRAF, ERBB2. We hypothesize that these mutations
may cooperative with PIK3CA and be associated with resistance to
endocrine therapy.
We have recently generated a novel mutant mouse with which to
study the role of the common tumour-associated PI3K mutation,
PIK3CAH1047R. We can also induce the expression of the mutation
in cells growing in culture allowing us to examine the effects of
PIK3CAH1047R mutation in vitro with and without other mutations
under defined conditions.
results can be devastating and may culminate in the development of
cancer. Importantly, recent efforts to annotate various cancer genomes
have brought into focus a new central theme in cancer biology:
recurrent mutations in epigenetic regulators, which are especially
prevalent in the haematopoietic cancers.
Our laboratory is focussed on understanding the molecular
mechanisms governed by epigenetic pathways in normal and malignant
haematopoiesis. In particular we explore how abnormal regulation of
certain epigenetic regulators can result in the initiation and maintenance
of haematological malignancies. We aim to use some of these insights
to develop and characterise novel epigenetic therapies for various
haematopoietic cancers. Our broad research aims include:
broad range of genomic, molecular biology and biochemical techniques
including RNA-Seq, ChIP-Seq, molecular cloning, quantitative realtime PCR, western blotting and biochemical purification of chromatin
complexes. Finally as our aim is to develop novel therapeutics for AML
we will also perform a range of in vivo studies using sophisticated
murine models of AML.
References:
1. MA Dawson et al. (2009) Nature. 461(7265): 819-22.
2. MA Dawson et al. (2011) Nature. 478(7370): 529-33.
3. MA Dawson et al. (2012) Cell. 150(1):12-27.
• Therapeutic targeting of epigenetic proteins in haematological
malignancies.
4. MA Dawson et al. (2012) New England Journal of Medicine.
367(7):647-57.
• Functional characterisation of the role that epigenetic regulators play
in normal haematopoietic stem cell renewal and in leukaemia stem cell
renewal.
For more information about potential projects contact: Dr Mark
Dawson. [Currently based at the University of Cambridge, UK] Tel: +44
1223334111, Email: [email protected]
• Investigation of the molecular mechanisms by which epigenetic
regulators direct cell fate decisions in haematopoiesis.
MOLECULAR THERAPEUTIC AND BIOMARKERS
TARGETING EPIGENETIC READERS IN ACUTE MYELOID
LEUKAEMIA
Supervisor: Dr Mark Dawson
Acute Myeloid Leukaemia (AML) is a heterogeneous disease at the
clinical, biological and molecular level, however unifying pathogenic
themes exist. It is characterised by transcriptional dysregulation leading
to a block in differentiation and increased self-renewal. Knowledge of
the molecular lesions associated with specific subtypes of AML has led
to the introduction of targeted therapeutics. However, despite some
progress, the management of AML remains an unmet clinical need,
with over 70% of patients still succumbing to the disease. Recently,
our evolving knowledge of the cancer genome has brought into focus
a central theme, that of recurrent mutations in epigenetic regulators,
which are especially prevalent in AML. Epigenetics is a term broadly
used to describe the study of chromatin biology. The dynamic plasticity
of the epigenome lends itself well to therapeutic manipulation.
This project aims to exploit this, by extending our recent discovery
of the therapeutic efficacy of BET (Bromodomain and extra terminal
protein) inhibitors in MLL-leukaemias (Dawson et al, Nature 2011) to
other forms of AML. The project will involve a diverse range of cell
biology techniques including cell culture and clonogenic assays with cell
lines and primary human / murine leukaemia cells, modulation of these
cells with shRNAs and small molecule inhibitors. We will also employ a
In the Molecular Therapeutics and Biomarkers Laboratory we perform
preclinical and translational studies aiming to develop and evaluate new
treatment strategies and predictive markers for cancer patients with
a focus on non-small cell lung cancer (NSCLC) and head and neck
squamous cell carcinoma.
Our group works at the interface between the clinic and laboratory to
• develop novel treatment strategies involving molecularly targeted
therapies that can be evaluated in clinical trials and
• conduct biomarker analyses on tissue samples collected from clinical
trials and archival sources to find better ways to select patients for
optimal treatment with conventional or novel oncology agents
The laboratory collaborates with the Tumour Suppression Laboratory,
under Professor Ygal Haupt, sharing an interest in investigating the
molecular mechanisms at work when the powerful tumour suppressor
gene, p53, is switched off in cancer; efforts to reverse this process
represent a promising new avenue for possible therapeutic intervention
We currently have several projects based around these themes that we
would like to discuss with students.
For more information about these projects contact: Assoc. Prof. Ben
Solomon, Tel: +61 3 96561118 , Email: [email protected]
The student will isolate and culture mammary epithelial cells from our
PIK3CAH1047R mouse and use these to examine how other mutations
cooperative with PIK3CA and if they can induce endocrine therapy
resistance. A broad range of techniques may be used: including tissue
culture, cloning and retroviral transduction, immunohistochemistry,
immunofluorescence, and western blotting, in vitro and in vivo assays
to assess functional activity such as proliferation, apoptosis, and
tumourigenesis, as well as analyses of human breast cancer samples
(DNA extractions and genomics techniques ie next generation
sequencing) and understanding of the management of breast cancer
patients.
For more information about this project contact: Dr Sherene Loi, Tel:
+61 3 9656 3642; Email: [email protected]
CANCER EPIGENETICS
Epigenetics is a term that is most commonly used to describe
chromatin-based events. Chromatin is a macromolecular complex
of DNA and histone proteins that exists in eukaryotic cells. The basic
functional unit of chromatin is the nucleosome, which consists of a
histone octamer around which DNA is wrapped. Chemical modification
of both histones and DNA occurs through highly conserved enzymes,
and these modifications are in turn “read” by epigenetic reader proteins.
The information conveyed by epigenetic modifications plays a critical
role in the regulation of all DNA-based processes, such as transcription,
DNA repair, and replication.
Epigenetic pathways such as DNA methylation, histone modification,
nucleosome remodeling, and non-coding RNA-mediated targeting
regulate many biological processes that are fundamental for normal
development. When these highly conserved epigenetic pathways are
corrupted by somatic mutations or abnormal gene expression the
Page 16
2014 Peter Mac Student Projects
Page 17
CANCER IMMUNOLOGY RESEARCH PROGRAM http://www.petermac.org/research/conducting-research/cancer-immunology
Laboratory Heads: Professor Joe Trapani, Assoc. Prof. Michael Kershaw, Assoc. Prof. Phil Darcy, Assoc. Prof. David Ritchie and
Dr Paul Neeson, Dr Sarah Russell
The Cancer Immunology Program is identifying ways in which the immune system can be harnessed to prevent and control cancer.
We are interested in the very early stages of how immune cells can pick up and respond to the presence of cancer cells. We have
demonstrated that specific toxins made by “killer T cells” can prevent the onset of certain cancers (immune surveillance), and are
developing genetic technologies to modify and expand the activity of these cells to treat established malignancies. In addition, we are
defining the molecular means by which new classes of anti-cancer drugs kill cancer cells, so that rational choices can be made on
the most appropriate cancer chemotherapy for a patient.
CANCER CELL DEATH & KILLER CELL BIOLOGY
REGULATION AND FUNCTION OF CYTOTOXIC LYMPHOCYTES
Supervisors: Prof. Joe Trapani, Dr. Ilia Voskoboinik, Dr. Misty Jenkins
and Dr. Jamie Lopez
Cytotoxic lymphocytes recognize and kill cancerous and virus-infected
cells through cytotoxic granule exocytosis pathway. Cytotoxic granules
store a pore-forming protein, perforin, and serine proteases, granzymes.
Once released, perforin transiently disrupts a target cell membrane thus
permitting the delivery of granzymes into the cytosol, where they initiate
various apoptotic death pathways. This is a fundamental homoeostatic
process and, when disrupted, has catastrophic consequences: it
either leads to fatal hyperinflammation or, in milder cases, results in
haematological malignancies in childhood or adolescence.
We investigate: (i) the regulation of cytotoxic granule exocytosis, (ii) the
structural bases of perforin pore formation, (iii) the biology of granzymes,
(iv) the molecular bases of congenital immune deficiency Familial
Haemophagocytic Lymphohistiocytosis, (v) the genetic predisposition to
haematological malignancies.
We offer project(s) in each of these areas, and a specific topic will
be selected to cater for the interests and skills of a candidate. A
prospective student will be a part of a successful multidisciplinary
research team of immunologists, biochemists, cell biologists, geneticists
and clinical scientists, and will gain experience in immunology, cell
biology (including various microscopy techniques), molecular biology
and biochemistry.
For more information about projects contact: Dr. Ilia Voskoboinik,
Tel: +61 3 9656 1657 or +61 3 9656 3725, Email: ilia.voskoboinik@
petermac.org
IMMUNE INNOVATION
TURNING CANCER AGAINST CANCER
Supervisor: Assoc. Prof. Michael Kershaw
Tumours are a mass of cancer cells in association with other cells,
termed stroma. Cancer cells are in close contact with each other in
tumours, and they tolerate each others presence and indeed can
benefit from each other. At the forefront of a tumour, cancer cells
interact with normal tissues and this interaction leads to invasion and
destruction of normal tissue. While metabolic competition, enzymes and
inflammatory molecules have been identified as potential contributors
to tissue invasion, the character and extent of tumour cell responses
against other cells is not well characterized. Nevertheless, cancer cells
express a variety of cell surface molecules and intracellular adaptor/
linker molecules that are able to mediate biological responses if
triggered appropriately. In this project, we want to see what happens
when these molecules in some cancer cells are specifically triggered
against the breast cancer molecule Her2 on neighbouring cancer cells.
Essentially, we want to try and turn cancer against itself. This will initially
involve making a gene encoding a chimeric cancer-subverting molecule
(CCSM) and inserting this gene into a proportion of cancer cells. These
cancer cells would then express the CCSM on their surface and could
respond against neighbouring Her2-positive cancer cells.
This approach could promote an attack on cancer from within its own
ranks. Conceivably, the effect on neighbouring cancer cells could be
direct, via cell contact or by secretion of specific molecules, or indirect
through disruption of tumour architecture and nutrient supply. In the
clinical application of this approach, two approaches are possible.
Firstly, a gene could be delivered to a proportion of cancer cells.
2014 Peter Mac Student Projects
Secondly, a bispecific reagent could be developed that links the cancer
subverting molecule to the target molecule (e.g. Her2).
In this research proposal we aim to test proof-of-principle using model
systems in vitro and in mice. Molecular biology techniques will be used
to make a series of genes encoding CCSMs. Lines of breast cancer
cells will be genetically modified in vitro to express CCSMs. Another line
of the same breast cancer cells will be established expressing Her2.
The effect of CCSM cells on Her2 cells will be determined in vitro using
flow cytometry and microscopy for Honours projects, which would
extend to studies in mice for higher degree studies.
For more information about this project contact: Assoc. Prof. Michael
Kershaw, Tel: +61 3 9656 1177; Email: [email protected]
SENSORY NEURONS AS CONDUITS FOR DELIVERING THERAPY
FOR PROSTATE CANCER.
Supervisor: Assoc. Prof. Michael Kershaw
Since prostate tumors and metastases are neurotropic and innervated,
we wish to test the hypothesis that neurons can be modified to express
molecules that can exert antitumor activity against prostate cancer. This
proof-of-principle study would involve genetically modifying neurons
isolated from mouse dorsal root ganglion cells using adeno-associated
virus vectors (AAV). DRG cells most faithfully replicate the structure
and morphology of primary neurons, which originate in the DRG and
have axons extending to tissues and ending in neurites that monitor
tissues. Genes with anti-tumor potential including Fas ligand and TRAIL,
cell surface cell death-inducing molecules, and interferon-gamma, a
secreted molecule with apoptotic and immune-stimulating properties,
will be used.
We will firstly determine the expression of these genes at the subcellular
level, particularly in neurites, since it is neurites that infiltrate tumors
most extensively. Confocal microscopy and flow cytometry will be
used to detect expression. Secondly, we will determine the ability of
gene-modified DRG cells to impact on Fas-positive prostate cancer
cells in vitro. 2-D cultures and 3-D collagen matrix cultures, together
with microscopy, flow cytometry and apoptosis assays, will be used
to determine the effect of gene-modified neurons on cancer cells. For
higher degree studies, a mouse model of prostate cancer bone tumors
will be used to determine the in vivo effect of genetically modifying
neurons for cancer treatment. DRG supplying the femurs of mice will
be injected with AAV vectors encoding Fas-L and/or IFN-gamma.
Expression and function of transgenes in neurons will be determined,
and the effect on tumor growth and normal tissues monitored. Previous
gene modification studies of neurons have focused on pain-related
issues. However, the proposed studies into using neurons as a means
of delivering cancer therapy are entirely novel.
For more information about this project contact: Assoc. Prof. Michael
Kershaw, Tel: +61 3 9656 1177; Email: [email protected]
IMMUNOTHERAPY
NOVEL COMBINATION IMMUNOTHERAPY FOR THE TREATMENT
OF CANCER
Supervisors: Dr. Paul Beavis, Assoc. Prof. Phil Darcy
It is now accepted that the immune system plays a fundamental role
in the elimination of cancer. Moreover, conventional therapies such
as radiotherapy and some chemotherapies are efficacious, in part,
due to their induction of immune responses. However, tumors utilize
mechanisms to evade the immune response. Significant therapeutic
opportunity exists in targeting these pathways thereby modifying the
Page 18
tumor environment from immunosuppressive to immune-activating. The
potential of this strategy is underlined by the recent FDA approval of
ipilimumab (anti-CTLA-4 mAb) to treat metastatic melanoma.
multicolour flow cytometry, cell culture and molecular biology
techniques, mice that are genetically modified to alter asymmetric cell
division, and tumour models to address these questions.
One such immunosuppressive mechanism is the generation of
adenosine by CD73, an enzyme expressed on the cell surface of
tumor cells. Our preliminary data indicates that blockade of adenosine
receptors using a small molecule inhibitor can enhance the anti-tumor
T cell response generated by the chemotherapeutic doxorubicin,
leading to prolonged survival of mice. We propose to extend this
study to investigate whether blockade of adenosine receptors can act
synergistically with other immunotherapies such as anti-41BB mAb,
anti-PD1 mAb and adoptive T cell transfer. The project will therefore
seek to identify novel combination therapies that may have clinical
relevance and consequently investigate the mechanism by which the
anti-tumor immune response is enhanced.
For more information about this project contact:
The project will involve a number of molecular and biochemical
methods including flow cytometry, ELISA and ex vivo stimulation of
isolated immune subsets. The student will become competent in tissue
culture and the handling of mice. We are looking for a highly motivated
student with an interest in immunology and the development of cancer
therapeutics.
For more information about these project contact: Dr Paul Beavis,
Email: [email protected]; Assoc. Prof. Phil Darcy, Email: phil.
[email protected]
GENERATION OF A TRIPARTITE CHIMERIC SINGLE CHAIN
RECEPTOR FOR ENHANCING ADOPTIVE T CELL IMMUNOTHERAPY
Supervisor: Assoc. Prof. Phil Darcy
Adoptive immunotherapy involving genetic modification of T cells with
TCR genes or single-chain (scFv) chimeric receptors is emerging as
a promising approach to specifically direct their activity toward tumour
cells1,2. Recently we have shown that chimeric receptors comprising
the co-stimulatory CD28 signalling domain linked in tandem with the
CD3- domain (scFv-CD28-) could optimally trigger T cell function in
vitro and in vivo. Nevertheless, these gene-engineered T cells were
less effective against established subcutaneous disease. A potential
approach to improve anti-tumour function of adoptively transferred
gene-engineered T cells is to increase their survival and persistence.
Signalling molecules from TNF receptor family that include OX-40,
CD27 and 4-1BB, play an important role in both survival of T cells
following activation and generation of an effective memory response.
Hence, in this project, we propose to test whether incorporation of
these various signalling molecules from the TNF receptor family into
our existing chimeric receptor design (tripartite receptor) can enhance
survival and anti-tumour activity of gene-modified T cells.
The project will involve a number of molecular and biochemical
methods including DNA cloning, sequencing, flow cytometry, ELISA,
cytokine and proliferation assays. The student will also become
competent in tissue culture (retroviral transduction of T cells and tumour
cells) and handling of mice. We are looking for a highly motivated
student who is interested in developing effective treatments for cancer.
References
1. Morgan RA, Dudley ME, Wunderlich JR, et al. Cancer regression in
patients after transfer of genetically engineered lymphocytes. Science
2006;314:126-9.
Dr. Sarah Russell, Tel: +61 3 9656 3727, Email: sarah.russell@
petermac.org
SUPER-RESOLUTION MICROSCOPY TO DISSECT CANCER
SIGNALING PATHWAYS
Supervisors: Dr Sarah Russell, Dr Ye Chen
Cancer therapies operate by disrupting signaling pathways that
allow the cancer cells to survive and proliferate. Recent advances
in our understanding of cancer cell signaling has led to dramatically
improved therapies, setting a paradigm to guide further research. New
imaging technologies: ‘super-resolution imaging’, have recently been
developed which have transformed the research on signaling pathways.
In a collaboration between biologists at Peter Mac and physicists
at Swinburne University, we have developed a super-resolution
imaging approach to determining the signaling pathways of a tumour
suppressor protein, Scribble. The student will apply these approaches
to understanding how this recently discovered tumour suppressor
interacts with oncogenic signaling molecules. This multidisciplinary
project will pave the way for development of new therapeutic modalities
to treat cancer.
For more information about this project contact: Dr. Sarah Russell, Tel:
+61 3 9656 3727, Email: [email protected]; Dr. Ye Chen, Tel:
+61 3 9214 5649, Email: [email protected]
INVESTIGATING THE IMMUNOLOGICAL SYNAPSE AND THE ROLE
OF EFFECTOR/MEMORY T LYMPHOCYTES IN ANTI-TUMOUR
IMMUNITY
Supervisor: Dr Jane Oliaro
Our laboratory studies the role of signaling and polarity proteins in T
lymphocyte biology. Polarity - or the compartmentalisation of proteins
within a cell - is critical for T lymphocyte functions such as migration,
immunological synapse formation and cytotoxic activity during an
immune response. More recently, we have shown that that asymmetric
cell division of T lymphocytes in response to antigen presentation may
be used to generate effector and memory T lymphocytes - a process
regulated by polarity proteins in other cell types.
A project is available to investigate the role of proteins involved in
immunological synapse formation in the regulation of anti-tumour
responses by the adaptive immune system. The immunological
synapse is critical for the activation of T lymphocytes, and for cytotoxic
activity against infected and cancerous cells. The project will utilise
knock out mouse models and in vitro culture systems to elucidate the
role of the immunological synapse in effector/memory T lymphocyte
responses, and how this impacts on anti-tumour immunity. The project
will involve some animal experimentation, immunological techniques
such as tissue culture and flow cytometry, and both fixed and live
imaging of cells using our state of the art microscopy facilities.
For more information about this project contact: Dr. Jane Oliaro, Tel:
+61 3 9656 1657, Email: [email protected]
2 Kershaw MH, Westwood JA, Darcy PK. Gene-engineered T cells for
cancer therapy. Nat Rev Can 2013 Aug;13(8):525-41.
IMMUNE SIGNALLING
A NEW MECHANISM FOR ONSET OF LEUKEMIA
Supervisors: Dr Sarah Russell, Dr Sarah Ellis
Cancer can arise when the balance between differentiation and
proliferation is disturbed, and understanding how this balance is
normally maintained is essential to combat
cancer. In epithelial tumours it is now clear that disruptions in
asymmetric cell division (the differential distribution of molecular cell
fate determinants into the two daughters of a dividing cell) can lead to
cancer by altering this balance. We have recently found that blood cells
also undergo asymmetric cell division, and that asymmetric cell division
is altered in mice that are predisposed to leukemia. An Honours and a
PhD project are available to determine how alterations in asymmetric
cell division impact upon cell fate decisions such as self-renewal,
proliferation, apoptosis and differentiation, and how this predisposes
to cancer. You will use state of the art time lapse imaging approaches,
2014 Peter Mac Student Projects
Page 19
CELL BIOLOGY RESEARCH PROGRAM Grzeschik et al. (2010) Cell Cycle 9(16):3202-12.
Parsons et al. (2010) Fly Oct; 4(4):288-93.
http://www.petermac.org/research/conducting-research/cancer-cell-biology
Laboratory Heads: Assoc. Prof. Helena Richardson, Assoc. Prof. Kieran Harvey, Dr Louise Cheng, Dr Patrick Humbert, Assoc. Prof.
Robin Anderson, Assoc. Prof. Pritinder Kaur, Prof Roger Martin, Prof. Ygal Haupt, Prof. Rob Ramsay
Diverse areas of cellular and molecular biology important in cancer are being explored within the Cell Biology program. We are
looking at regulation of the cell cycle, the signalling pathways within tumour cells and host cells adjacent to tumours that drive tumour
growth and metastasis and the importance of the aberrant regulation of apoptosis in tumour cells. Since radiotherapy is a major
treatment modality for cancer, we are investigating how radiation kills cells and ways to improve the application of this therapy to
patients.
CELL CYCLE AND DEVELOPMENT
The cell cycle and development lab uses sophisticated genetic and
cell biological analysis of the animal model system, the vinegar fly
Drosophila, to address fundamental questions in cancer biology.
ANALYSIS OF COOPERATING TUMOURIGENESIS USING
DROSOPHILA
Supervisors: Dr Kirsten Allan, Assoc. Prof. Helena Richardson
This project will address the fundamental cancer questions of how
cell shape regulators affect cell proliferation, survival and tumour
progression. Our lab is a dynamic lab, with researchers at all stages
of their careers. The project will be supervised by Dr Kirsten Allan who
has extensive experience in working in Drosophila and in supervising
students. This project will suit those who enjoy working on model
systems that can be readily manipulated.
The project will focus on addressing the functional importance of
Rho-family proteins and effectors in cell polarity mutant mediated
tumourigenesis. We have already shown that activation of Rho and the
effectors Rok and MyoII cooperate with oncogenic Ras in Drosophila
neural-epithelial cells, but now seek to determine their requirement in
tumourigenesis with mutants in cell polarity regulators, such as Lgl,
Scribbled, Dlg, aPKC and Crumbs. The project will involve genetic,
biochemical and cell biological approaches.
References:
Khoo et al (2013) Disease Models & Mechanisms May; 6(3):661-78.
Brumby, et al (2011) Genetics May, 188(1):105-25.
Brumby & Richardson (2003) EMBO J. 22:5769-79.
Brumby & Richardson (2005) Nature Reviews Cancer, 5: 626-39.
For more information about this project contact: Assoc. Prof. Helena
Richardson, Tel: +61 3 9656 1466, Email: helena.richardson@
petermac.org
COOPERATIVE TUMOURIGENESIS: ANAYSIS OF NOVEL TUMOUR
SUPPRESSORS IN RAS ONCOGENE DRIVEN EPITHELIAL
TUMOURS
Supervisors: Dr Jan Manent, Assoc. Prof. Helena Richardson, Dr
Patrick Humbert and Dr Kaylene Simpson
This project will suit those who are interested in a holistic understanding
of cancer and with an interest in modeling cancer. The project will
encompass a wide range of cell biology (microscopy), biochemistry,
genetics and molecular biology techniques. The project will be
supervised by Dr Jan Manent, who has extensive experience in
Drosophila and mammalian molecular genetics, biochemistry and cell
biology.
We have carried out a genetic screen in flies for novel tumour
suppressors that cooperate with the Ras oncogene to promote invasive
overgrowth of neural-epithelial tissue. This project will use sophisticated
Drosophila genetics, and molecular, cell biology and biochemical
approaches to determine how one of these novel tumour suppressors
affects the hallmarks of cancer in vivo in Drosophila. The project will
extend into the analysis of the mammalian homolog of this gene in
tumourigenesis in mammalian epithelial cells, in collaboration with Drs
Patrick Humbert and Kaylene Simpson.
References:
Turkel et al (2013) PLoS Genetics
Brumby, et al (2011) Genetics May, 188(1):105-25.
2014 Peter Mac Student Projects
Brumby & Richardson (2003) EMBO J. 22:5769-79.
Brumby & Richardson (2005) Nature Reviews Cancer, 5: 626-39.
Humbert et al., (2010) Oncogene, 27:6888-6907.
Cheng et al. (2013) Enc Life Science March 15
For more information about this project contact: Assoc. Prof. Helena
Richardson, Tel: +61 3 9656 1466, Email: helena.richardson@
petermac.org; Dr Jan Manent, Email: [email protected]
ANALYSIS OF DROSOPHILA MODELS OF BRAIN CANCER
Supervisors: Dr Kirsten Allan, Assoc. Prof. Helena Richardson
We are using genetic and cell biological approaches to model
human brain cancers in Drosophila. In particular we are interested in
understanding the importance of regulators of cellular architecture,
including the actin cytoskeleton, in the tumourigenic properties of these
cancers. The project will involve the use of transgenic over-expression
or RNAi Drosophila lines and small molecule inhibitors to assess the
importance of cytoskeletal regulators in brain tumour models.
The project will be supervised by Dr Kirsten Allan who has extensive
experience in Drosophila and supervising students. The project will
suit those who are interested in a holistic understanding of cancer and
enjoy working on genetically tractable model organisms. The project
will encompass a wide range of cell biology (microscopy), biochemistry,
genetics and molecular biology techniques.
References:
Brumby, A.M. et al (2011) Genetics May, 188(1):105-25.
Brumby & Richardson (2005) Nature Reviews Cancer, 5: 626-39.
Cheng et al. (2013) Enc Life Science March 15
For more information about this project contact: Assoc. Prof. Helena
Richardson, Tel: +61 3 9656 1466, Email: helena.richardson@
petermac.org
Humbert et al. (2010) Oncogene, 27:6888-6907.
• How does diet and nutrition affect tumour growth?
Elsum et al (2012) Essays in Biochemistry. Aug 10; 53(1):141-68.
• What are the metabolic changes that take place in the tumours?
For more information about this project contact: Assoc. Prof. Helena
Richardson, Tel: +61 3 9656 1466, Email: helena.richardson@
petermac.org
• What are the metabolic changes that take place within the host in
response to tumour growth?
CELL GROWTH & PROLIFERATION
For more information about this project contact: Dr Louise Cheng, Tel:
+61 3 9656 5285, Email: [email protected]
THE HIPPO PATHWAY, REGENERATION AND CANCER
CELL CYCLE AND CANCER GENETICS
Supervisor: Assoc. Prof. Kieran Harvey
INVESTIGATING THE MOLECULAR LINK BETWEEN BRCA2 LOSS
AND PROSTATE CANCER
In the Cell Growth and Proliferation laboratory we are interested in
how tissue growth is controlled during development and regeneration.
We are also interested in how deregulation of signalling pathways that
control tissue growth contributes to the genesis of human cancer.
We utilise the model organism, Drosophila melanogaster (vinegar fly),
mouse models and mammalian cell culture to discover and investigate
genes involved in tissue growth and cancer. Our approach is to identify
genes involved in cancerous-like growth in flies and then use human
and mouse models to determine whether the human counterparts of
these fly cancer genes have a role in human cancer. Approximately
70% of human disease genes are conserved in flies, making it an
excellent model for these studies.
One newly identified signaling pathway that our laboratory helped to
discover and actively studies is the Salvador-Warts-Hippo (Hippo)
pathway, which controls organ size during development. This pathway
controls organ size by restricting cells from growing and dividing
excessively, properties central to the formation of cancer. The Hippo
pathway is conserved in humans and several studies from our
laboratory and others have implicated this pathway in the genesis of
human cancer (eg. Reference 4, below). By studying various aspects of
this pathway we aim to understand how organ size is correctly specified
during development, and how deregulation of this pathway contributes
to human cancer.
Broad research questions:
• How does the Hippo pathway control organ size.
• How does the Hippo pathway control human cancer.
We currently have several projects based around these aims that we
would like to discuss with students.
For more information about these projects contact: Assoc. Prof. Kieran
Harvey, Tel: +61 3 9656 1291, Email: [email protected]
References from our laboratory relevant to the project:
1. C. Poon et al., Current Biology. 17, 1587-1594.
2. C. Poon et al., Developmental Cell. 5, 896-906.
3. F. Grusche et al. (2011). Developmental Biology. 3550, 255-266.
4. X. Zhang et al. (2011). Oncogene. 30, 2810-2822.
HOW CELL POLARITY REGULATORS AFFECT SIGNALLING
PATHWAYS
5 F. Grusche et al. (2010). Current Biology. 20, r574-582.
Supervisors: Dr Linda Parsons, Dr Marta Portela, Assoc. Prof. Helena
Richardson and Dr Patrick Humbert
6. C. Milton et al. (2010). Development. 137, 735-43.
This project focuses on how signaling pathways are affected by the cell
polarity (shape) regulators, Lgl and aPKC in mediating their effects on
cell proliferation and survival. The project will be supervised by Drs Linda
Parsons and Marta Portela, who have extensive experience in working
with Drosophila, mammalian cells and supervising students. The
project will suit those who enjoy working on genetically tractable model
organisms and are interested in a holistic understanding of cancer.
The project will encompass a wide range of cell biology (microscopy),
biochemistry, genetics and molecular biology techniques.
8. F. Bennett and K.F. Harvey (2006). Current Biol. 16, 2101-2110.
Our previous research has shown that Lgl knockdown perturbs the
Hippo and Notch signaling pathways and suggests that Lgl may
regulate protein trafficking. The project will investigate the question
of how Lgl or aPKC affects the Notch signaling pathway and protein
trafficking in Drosophila. The project will include the analysis of Lgl or
aPKC protein interactors, determined by Mass Spec analysis by our
collaborator Dr Veraksa (Boston), in Drosophila and in mammalian cells
in collaboration with Dr Patrick Humbert.
Supervisor: Dr. Louise Cheng
7. X. Zhang et al. (2009). Cancer Research. 69, 6033-6041.
9. K.F. Harvey et al. (2003). Cell 114, 457-467.
10. N. Tapon et al. (2002). Cell 110, 467-478.
STEM CELL GROWTH REGULATION
METABOLIC REGULATION OF TUMOUR GROWTH
References:
Studies of neural stem cell biology in model organisms have revealed
many similarities in the regulation of self-renewal, multipotency and
cell-fate determination between vertebrate and invertebrates. We
use the fruit fly Drosophila as a model system to study the processes
that regulate proliferation in the central nervous system. When these
processes are disrupted, uncontrolled growth and proliferation result in
neural tumours.
Grzeschik et al. (2010) Curr Biol. 20 (7): 573-81.
Some of the questions we hope to address are:
Page 20
• What are the signals (cell autonomous and non-cell autonomous) that
drive the growth of the neural tumours?
2014 Peter Mac Student Projects
Supervisors: Dr Helen Pearson, Dr Patrick Humbert
The ability of cells to repair DNA damage is fundamental to retaining
genomic integrity as defects in the repair machinery can lead to genetic
instability and carcinogenesis. Breast Cancer Type 2 susceptibility
protein (termed BRCA2) is a component of a DNA repair mechanism
that fixes double-stranded breaks in DNA. Loss of BRCA2 function
results in reduced stability of genetic material, increasing the risk of
tumour-initiating mutations. BRCA2 is commonly mutated in familial
breast and ovarian cancers and has recently been identified as a
familial/hereditary prostate cancer gene. Men who inherit a mutation
in the BRCA2 gene are at a greater risk of developing prostate cancer
with their tumours displaying loss-of heterozygosity at the BRCA2
locus. These tumours are associated with a highly aggressive subtype
of the disease, with the vast majority of patients showing metastatic
disease at presentation.
Aided by molecular information from patients, you will utilize genetically
engineered mice to analyze a pre-clinical mouse model carrying
a BRCA2 mutation. In addition, you will also use patient tumours
themselves through transplantation into mice to generate personalized
pre-clinical models for these patients. These models will allow testing
of new therapies as well as providing molecular insights into the
tumourigenic mechanisms instigated by BRCA2 loss and prostate
cancer more broadly.
For more information about this project contact: Dr. Helen Pearson,
Tel: +61 3 9656 1358, Email: [email protected]; Dr. Patrick
Humbert, Tel: +61 3 9656 3526, Email: [email protected]
SYSTEMS BIOLOGY ANALYSIS OF THE CELL POLARITY NETWORK
IN BREAST CANCER
Supervisors: Dr Patrick Humbert, Dr Kaylene Simpson, Pr Edmund
Crampin (University of Melbourne)
Loss of the proper orientation of cells within a tissue, known as cell
polarity, is one of the hallmarks of epithelial cancer, and is correlated
with more aggressive and invasive cancers. However how loss of cell
polarity occurs and how it contributes at the molecular level to tumour
formation remains unknown.
This project aims to identify the cellular and molecular mechanism by
which the Cell Polarity gene network controls breast tumorigenesis. In
order to achieve this, our laboratory has carried out a variety of large
scale RNAi screens, as well as expression analysis in 3D organotypic
culture models and genetically engineered mouse models of cancer,
and accessed through our collaboration with Dr Helena Richardson
at the Peter Mac an extensive set of complementary genetic screens
and expression data focused on cell polarity and cancer in Drosophila.
Together with publically available proteomics and clinical genomics
information, these datasets provide a powerful base to build a
topological model of the gene network that regulate the tumour
suppressive functions of cell polarity genes.
In this project, you will use computational approaches to analyze and
characterize the network of genetic and physical interactions underlying
loss of polarity driven breast cancer with the ultimate aim of identifying
therapeutically targetable network nodes for these diseases. To test,
validate and elaborate this predictive model, you will use high content
RNAi screening approaches in conjunction with a suite of functional
assays set up in our laboratory. A better understanding of this pathway
and how loss of tissue architecture can occur and impact on cancer
progression will lead to the discovery of novel prognostic factors, novel
chemotherapeutic targets and fundamental insights into epithelial
tumour biology and cancer progression.
For more information about this project contact: Dr. Patrick Humbert,
Tel: +61 3 9656 3526, Email: [email protected]; Dr
Page 21
Kaylene Simpson. Tel: +61 3 9656 1790; Email: kaylene.simpson@
petremac.org
STRUCTURAL AND BIOCHEMICAL CHARACTERIZATION OF
POLARITY COMPLEXES IN CANCER
Supervisors: Dr Patrick Humbert, Dr Marc Kvansakul (La Trobe
University)
Every cell in our body has an intrinsic orientation (or polarity) that is
controlled by a universal set of genes known as polarity genes. Loss
of this orientation is a defining early feature in cancers, and has been
linked to cancer spread or metastasis. Our team has previously
identified the gene Scribble as a new human polarity gene that controls
cell orientation and whose levels appeared reduced in certain tumours
such as prostate tumours. Using mouse models and samples from
tumour patients we have shown that Scribble acts as a suppressor of
tumours. In particular, we have shown that lowering levels of Scribble in
normal cells increases the risk of cancer by disorganizing the tissue and
by increasing the speed at which cells grow within the tissue.
We now need to establish how Scribble and its biochemical partners
contribute to tumour formation and metastasis and clarify their
molecular mechanism of action, to enable targeting of these proteins
for therapeutic purposes. To achieve this, you will biochemically
characterize the interactions between Scribble and known and novel
biochemical partners using a variety of biochemical, high-resolution
imaging techniques and functional assays. Using X-ray crystallography,
you will show in atomic detail how they perform their function. Gaining
deeper insight into the nature of the interactions that allow Scribble
and its partners to perform its function will be critical to formulate novel
anti-cancer compounds that aim to exploit the loss of polarity in cancer
cells. All structural and biochemical information will be validated for
their functional relevance in our well established mouse and cellular
models, and therefore rapidly translated into biological information
directly relevant to human cancer patients and their outcome. These
studies investigating the mechanism of how the Scribble complexes
are formed will lead to the discovery of new prognosis factors and new
chemotherapeutic targets, as well as a better understanding of cancer
biology and cancer progression.
For more information about this project contact: Dr. Patrick Humbert,
Tel: +61 3 9656 3526, Email: [email protected]
HOW DO RED BLOOD CELLS ENUCLEATE?
Supervisor: Dr Patrick Humbert
Erythropoiesis involves the gradual progression of a hematopoietic
stem cell into a mature red blood cell. During terminal differentiation,
the proerythroblasts undergo several differentiation-linked cell divisions
with the erythroid cells finally exiting from the cell cycle and extruding
their nuclei in a process termed erythroid enucleation. The enucleation
event involves multiple pathways and shares some similarities with
cytokinesis and apoptosis. Indeed, this terminal differentiation of
erythroid cells may provide an extreme example of asymmetric division
where the final division gives rise to one daughter cell containing all of
the genetic material whilst the other daughter cell, the “enucleated”
daughter cell, will give rise to the functional erythrocyte population
required to provide oxygen to the organism. We have set up a powerful
in vitro erythroid differentiation system, high throughput chemical
genetics screening platform and in vivo genetic mouse models for the
analysis of enucleation. You will utilize these experimental systems to
perform systematic genetic and chemical screens to identify the key
stages and factors involved in the enucleation of erythrocytes. These
studies will provide fundamental insights into the regulation of erythroid
differentiation as well as identify factors that will facilitate the production
of de novo red blood cells critical for blood transfusion.
For more information about this project contact: Dr. Patrick Humbert,
Tel: +61 3 9656 3526, Email: [email protected]
FUNCTIONAL CHARACTERISATION OF NOVEL POLARITY AND
TUMOUR SUPPRESSOR GENES IN BREAST CANCER
Supervisors: Dr Nathan Godde, Dr Patrick Humbert
Loss of the proper orientation of cells within a tissue, known as cell
polarity, is one of the hallmarks of epithelial cancer, and is correlated
with more aggressive and invasive cancers. However how loss of cell
polarity occurs and how it contributes at the molecular level to tumour
formation remains unknown.
Our laboratory has investigated polarity regulators, such as Scribble,
that act as tumour suppressor genes. We have used a number
of approaches such as RNAi screening and have now identified a
network of genes that mediate the tumour suppressive functions of
2014 Peter Mac Student Projects
Scribble. The top candidate hits of these screens therefore represent
novel regulators of cell polarity, Ras signaling and/or novel tumour
suppressors.
This project aims to identify the cellular and molecular mechanism
by which these novel polarity and tumour suppressor genes regulate
breast tumorigenesis. In this project, you will characterize these
top key candidate hits using a variety of biochemical, cell biological
and functional assays set up in our laboratory. These include gene
knockdown studies in 3D mammary organoid cultures, use and
analysis of genetically engineered mouse models of breast cancer,
and mammary gland reconstitution experiments involving the surgical
transplantation of RNAi modified mammary stem cells into isogenic
recipient mice.
The above experiments will provide essential information as to the
requirement for intact polarity signaling in breast cancer development
and the molecular pathways regulated by Scribble to suppress invasion
and tumour growth. These studies will complement the systems
biology approaches used to map the network of interactions of polarity
regulators in our laboratory and allow the functional assessment of
the critical nodes in vivo that regulate cell polarity and breast cancer
progression.
For more information about this project contact: Dr. Nathan Godde, Tel:
+61 3 9656 1358, Email: Nathan [email protected]; Dr. Patrick
Humbert, Tel: +61 3 9656 3526, Email: [email protected]
METASTASIS RESEARCH
CHARACTERISATION AND VALIDATION OF A NEW MOUSE MODEL
OF SPONTANEOUS HER2+VE METASTATIC BREAST CANCER
Supervisor: Dr. Normand Pouliot
Breast cancer can be divided into several molecular subtypes,
each with a distinct metastatic propensity. The “HER2 subtype”
overexpresses the human epidermal growth factor receptor-2 (HER2)
due to gene amplification. HER2 tumours are very aggressive, often
spread to brain and do not respond to standard hormone-targeted
therapies as they lack expression of hormone [estrogen (ER) and
progesterone (PR)] receptors. Novel therapies specifically targeting
HER2 have been developed but their efficacy against metastatic
disease is often compromised by the development of resistance.
Animal models are essential to investigate the mechanisms regulating
the metastatic spread of HER2 tumours and the development of
drug resistance. However clinically relevant HER2 mouse models
that replicate the biology and metastatic abilities of HER2 tumours
are lacking. We recently isolated a spontaneous mammary tumour
in an immune competent Balb/c mouse that phenotypically fits the
HER2 subtype. Most importantly recent work in our laboratory has
led to the development of highly metastatic HER2 tumour variants. To
our knowledge, these HER2+ve sublines are the first ever described
that aggressively metastasise to multiple organs from the mammary
gland in immune competent mice. They are therefore ideally suited
for mechanistic studies as well as for testing of novel therapies against
HER2 tumours in vivo. This project aims to:
1. Further characterise our novel metastatic HER2 mouse model
phenotypically and functionally and
2. Test the anti-metastatic efficacy of HER2-targeted therapies alone or
in combination with chemotherapy in vivo.
The project is suitable for both Honours and PhD students and will
make use of a variety of techniques ranging from basic cell culture,
in vitro functional assays (proliferation, migration, invasion, survival),
immunohistochemistry, fluorescence imaging, molecular techniques
and in vivo metastasis assays in mice.
For more information about this project contact: Dr. Normand Pouliot,
Tel: +61 3 9656 1285; Email: [email protected]
EPITHELIAL STEM CELL BIOLOGY
EPIDERMAL STEM CELLS AND THEIR MICROENVIRONMENT:
INVESTIGATION OF THE MOLECULAR REGULATORS OF NORMAL
SKIN REPLACEMENT, WOUND HEALING AND CANCER IN HUMAN
SKIN
Supervisors: Dr. Pritinder Kaur
Human skin epidermis is a constantly renewing tissue, where the
combined action of relatively quiescent keratinocyte stem cells and their
committed progeny undergo tightly regulated proliferation to replace
normal skin tissue. A hallmark of stem cells is the capacity to regenerate
Page 22
the tissue of origin for a prolonged period of time and to constantly selfrenew. Our lab recently demonstrated in long-term tissue reconstitution
assays that the greatest capability of tissue reconstitution resides
within the candidate keratinocyte stem cells. However, it is also clear
that stem cell properties such as self-renewal and tissue replacement
can be enhanced by cellular and molecular regulators found in the
microenvironment, although this remains poorly characterized. A dermal
cell type i.e. pericytes, isolated using specific antibodies and flow
cytometry can enhance the proliferative capacity of human keratinocyte
stem cells and their committed progeny independent of angiogenesis.
In epithelial cancers, pericyte involvement can predict cancer
progression and disease-free survival in patients despite treatment with
current cancer therapies.
Two projects are available for PhD students with the following aims:
1. Investigate the role of specific candidate molecules synthesised and
secreted by pericytes identified in our laboratory, that will improve the
growth of skin cells.
2. Investigate the role of the same molecules secreted by pericytes that
promote tumour growth in models of skin, ovarian and breast cancer.
Both projects use techniques routinely employed in our laboratory such
as tissue culture of primary cells, cell sorting using a fluorescenceactivated cell sorter, standard molecular and cell biological methods like
cloning or SDS-PAGE, as well as microscopy (light and electron) and
mouse models of tissue regeneration, cancer and wound healing.
The results of these studies will have the following impact on human
skin biology:
1. Increase understanding of how stem cells and their environment
manage to routinely replace skin cells
2. Understand how stem cells escape from regulatory mechanisms
that prevent cancer development
3. Understand the role of stem cells and their environment in promoting
wound healing
4. Improve current methods for expanding skin cells for transplantion
onto patients with large skin deficits e.g. burns patients.
5. Improve diagnosis of patients with aggressive epithelial cancers e.g.
ovarian & breast
For more information about this project contact: Dr. Pritinder Kaur, Tel:
+61 3 9656 3714; Email: [email protected]
MOLECULAR RADIATION BIOLOGY
RADIOPROTECTION OF MOUSE ORAL MUCOSA BY
METHYLPROAMINE ANALOGUES – EVALUATION OF 2-PYRIDYL
HOECHST PRODRUGS
Supervisor: Prof. Roger Martin, Dr Pavel Lobachevsky, Dr Andrea Smith
The normal tissue damage associated with radiotherapy has motivated
the development at Peter Mac of a new class of DNA-binding
radioprotecting drugs that could protect normal tissues at risk (eg
oral mucosa) when applied topically. The properties of DNA-binding
radioprotectors, however, impose severe handicaps for topical delivery,
mainly due to their positive charge and the presence of H-bond
donors and acceptors that affect penetration of drugs through the
superficial barrier of the target tissue. These properties can be modified
by derivatisation of the radioprotector molecule by addition of labile
promoieties that are released after penetration of the tissue barrier, to
produce the parent drugs in the vicinity of the target cells (eg basal
cells). The rate of production of the parent drug is a critical parameter
since on one hand, the prodrug should be relatively stable to penetrate
the superficial tissue barrier, and on other hand, labile enough for timely
release of the parent drug. The aim of the project is to synthesise
a collection of prodrugs of the methylproamine analogue 2-pyridyl
Hoechst, and investigate the rates of hydrolysis to the parent drug
and its uptake into basal cells of mouse oral mucosa following topical
application of the prodrug.
For more information about this project contact: Dr. Pavel Lobachevsky,
Tel: +61 3 9656 1290; Email: [email protected]
NEW DNA BINDING RADIOPROTECTORS: INVESTIGATION OF
FACTORS THAT AFFECT RADIOPROTECTIVE EFFICIENCY
Supervisors: Dr. Pavel Lobachevsky, Prof. Roger Martin
The normal tissue damage associated with radiotherapy has motivated
the development at Peter Mac of a new class of DNA-binding
2014 Peter Mac Student Projects
radioprotecting drugs to protect normal tissues at risk. Methylproamine,
the lead compound, decreases radiation induced cell death apparently
by reducing radiation-induced DNA damage. The screening of
the library of methylproamine analogues, aimed at improving their
radioprotective efficiency and reducing cytotoxicity, revealed a few
pairs of interesting compounds. These pairs are characterised by
a minor change in the chemical structure of the molecule, which
however results in almost complete loss of radioprotection in cell
culture. A few hypotheses have been suggested to account for such
change in radiobiological properties of these chemically closely related
compounds, such as the loss of the ligand’s ability to reduce radiationinduced DNA damage, the change in the ligand’s DNA binding affinity/
specificity, the change in the cellular and nuclear uptake of the ligand.
The aim of the project is to investigate these hypotheses. The project
involves studies of DNA binding affinity by spectrophotometric titration,
and measurement of the kinetics and concentration dependance of the
nuclear uptake of ligands, using both drug extraction and HPLC, and
fluorescent microscopy.
For more information about this project contact: Dr. Pavel Lobachevsky,
Tel: +61 3 9656 1290; Email: [email protected]
EVALUATION OF RADIOSENSITIVITY IN CANCER PATIENTS
TREATED WITH RADIOTHERAPY
Supervisors: Assoc. Prof. Olga Martin, Prof. Roger Martin and Dr. Pavel
Lobachevsky
Radiotherapy (RT) is a major treatment modality for more than half
of cancer patients. The RT doses, although tolerated by the vast
majority of patients, result in serious side effects for about 5% of
patients. Numerous attempts have been undertaken to develop
effective predictive assays to identify prospective RT patients with high
radiosensitivity (RS) by using normal tissues from RT patients, however
so far their clinical applicability is limited. We propose application of
gH2AX assay which reflects induction and processing of DNA damage
as a measure of RS. It has been established that RS is determined
to a large extent by the ability of cells to repair DNA double strand
breaks that is reflected in turn in the kinetics of the disappearance
of gH2AX foci. This kinetics pattern has been found to be altered in
lymphocytes of RS patients with deficient DNA damage repair systems,
however further validation of the assay is required and constitutes the
major aim of the proposed project. The project involves microscopical
investigation of gH2AX foci kinetics in irradiated blood lymphocytes from
retrospective RT patients and establishment of correlation between the
shape of the kinetics curve and the radiosensitivity status of a patient.
For more information about this project contact: Dr. Olga Martin, Tel:
+61 3 9656 1357; Email: [email protected]
INVESTIGATION OF MECHANISMS OF THE RADIATION-INDUCED
BYSTANDER EFFECT
Supervisors: Assoc. Prof. Olga Martin, Dr Pavel Lobachevsky
The discovery of the radiation-induced bystander effect (RIBE) has
challenged the central dogma of radiation biology; that biological effects
of ionising radiation is proportional to radiation dose and therefore
limited to directly irradiated cells. Now, the RIBE is a well-established
consequence of radiation and is manifested as increased genomic
abnormalities and loss of viability of unirradiated (“bystander”) cells
associated with the targeted cells. A similar phenomenon, reported
by cancer radiotherapists, defined as a change in an organ or tissue
distant from the irradiated region, was termed the abscopal effect.
Since these non-targeted effects include malignant transformation, the
RIBE represents a serious risk factor in radiotherapy, which is part of
the treatment of about half of all cancer patients. In vitro studies indicate
that the signalling molecules include pro-inflammatory cytokines and
longer-lived free radicals. It has been suggested that the activation
of inflammatory macrophages through the cytokine CCL2 can be a
major mechanism of the RIBE in vivo. We can test this hypothesis
using CCL2 knock-out (KO) mice. If the hypothesis is supported by
experimental data, then CCL2 would represent a potential “risk marker”
for radiotherapy planning.
The proposed project, sponsored by an NHMRC project grant, will
use tissues collected from mice locally irradiated at the Imaging and
Medical Beamline (IMBL) at the Australian Synchrotron. This facility
is one of only three in the world configured for a wide range of biomedical research studies including both humans and small animals.
This includes the capability to investigate a promising new RT modality,
microbeam radiotherapy (MRT), in which the X-ray beam is split into
an array of planar parallel microbeams, only achievable in synchrotron
facilities. MRT has been shown to induce less pronounced effects
in irradiated normal tissues compared to tumours. We will compare
MRT with normal, broad beam (BB) synchrotron X-rays, with respect
Page 23
to induction of RIBE in mice, to establish whether MRT also induces a
long-range RIBE. A thorough study of RIBE as a function of irradiated
tissue volume, radiation dose, beam configuration and time has never
been performed to date. We will extend the investigation of the RIBE
by determining the influence of these parameters on the RIBE, and
tracking the kinetics of its appearance in wild-type and CCL2 KO mice.
The results could prompt a similar study with conventional radiation,
and if confirmed in that setting, would have a profound effect on the
planning of cancer radiotherapy regimes, so as to minimize the RIBE.
For more information about this project contact: Assoc. Prof. . Olga
Martin, Tel: +61 3 9656 1357; Email: [email protected]
PRODRUGS OF DNA BINDING RADIOPROTECTORS – WHY THEY
RETAIN RADIOPROTECTIVE PROPERTIES IN CULTURED CELLS
Supervisors: Dr Pavel Lobachevsky, Prof. Roger Martin, Dr Andrea
Smith
The normal tissue damage associated with radiotherapy has motivated
the development at Peter Mac of a new class of DNA-binding
radioprotecting drugs that could protect normal tissues at risk (eg
oral mucosa) when applied topically. DNA-binding radioprotectors,
however, show limited ability to penetrate the superficial barrier of the
target tissue. The efficient topical delivery is achieved therefore by
derivatisation of the radioprotector molecule (parent drug) by addition
of labile promoieties that enable penetration of the tissue barrier. Since
the derivatised molecule (prodrug) lacks DNA binding and therefore
radioprotecting ability, the promoieties have to be released following
tissue penetration to release the parent drugs in the vicinity of the
target cells (eg basal cells). Radiobiological studies with prodrugs using
cultured cells have demonstrated that some of the relatively stable
prodrugs unexpectedly retain the radioprotection ability that even
exceeds the extent of radioprotection by their counterpart parent drugs.
Investigation of the mechanism of this phenomenon that is not yet
understood represents the main aim of the proposed project.
The project will include studies of radioprotection using clonogenic cell
survival end point; kinetics of the uptake and the chemical form of (pro)
drugs in cells and nuclei using fluorescence microscopy and isolation
of drugs from cells and nuclei followed by HPLC analysis; DNA binding
by spectrophotometric titration; chemical stability of prodrugs in various
environments such as solutions of different pH and cell culture medium
and the role of biological enzymes in the release of parent drug using
HPLC analysis.
For more information about this project contact: Dr. Pavel Lobachevsky,
Tel: +61 3 9656 1290; Email: [email protected]
TUMOUR SUPPRESSION
The major goal of our research is to define the critical regulatory nodes
in tumour suppression, and to translate this information to design new
approaches to anti-cancer treatments. The work in our lab focuses
on the regulation of two key tumour suppressors, p53 and PML
(promyelocytic leukemia protein), following our discovery of how they
are destroyed (Haupt et al., 1997 Nature; Luoria-Hayon et al., 2009,
CDD). We are using this information to manipulate these tumour
suppressors in order to restore their activities to achieve selective
killing of cancer cells. We use a variety of in vitro and vivo experimental
systems and advanced technologies in our research. We are seeking
Honours and PhD students to undertake exciting research projects
addressing these areas of research.
EXPLORATION OF NOVEL APPROACHES TO ANTI-CANCER
TREATMENT: MANIPULATION OF MUTANT P53
Supervisors: Dr. Sue Haupt, Prof. Ygal Haupt
We have recently identified novel regulators of mutant p53. In this
project the PhD candidate will study key regulators of mutant p53 to
which cancer cell have become “addicted”. The candidate will explore
the efficacy of manipulating these regulators as a novel approach to
treating cancer cells bearing mutant p53 (majority of human cancers).
The project will involve work with cancer cell lines and transgenic
mouse models. In addition the project will expose students to a variety
of molecular, cellular and biochemical techniques.
2014 Peter Mac Student Projects
For more information about this project contact: Dr. Sue Haupt, Email:
[email protected]; Prof. Ygal Haupt, Tel: +61 3 9656 5871;
Email: [email protected]
INVOLVEMENT OF MDMX IN HUMAN CANCER: THERAPEUTIC
IMPLICATIONS
Supervisors: Dr. Sue Haupt, Prof. Ygal Haupt
Mdmx is a key and independent inhibitor of the tumour suppressor
p53. While Mdmx acts together with Mdm2 (the E3 ligase of p53) to
promote p53 degradation, it acts as a powerful inhibitor of p53 activity
without promoting it for degradation. Mdmx expression is elevated in
various sarcomas and other solid tumours by amplification and other
mechanism. However, recent findings shows that it can be elevated
at the protein level as well in melanoma (Nature Medicine 2012). We
have recently extended this finding to other cancer types. In this project
the candidate will determine whether targeting Mdmx is a valuable
approach to reactive p53 in specific cancer types. The project will
involve work with cancer cell lines and mouse models, and employ a
variety of molecular, cellular and biochemical techniques.
For more information about this project contact: Dr. Sue Haupt, Email:
[email protected]; Prof. Ygal Haupt, Tel: +61 3 9656 5871;
Email: [email protected]
RESTORATION OF TUMOUR SUPPRESSION BY USING THE
UBIQUITIN PROTEASOMAL SYSTEM AS AN ANTI-CANCER
APPROACH
Supervisors: Dr Kamil Wolyniec, Prof. Ygal Haupt
A link between proteasomal degradation of proteins and cancer
has been firmly established. Specifically, the degradation of tumour
suppressors by oncogenic E3 ligases is a key step during cancer
development. This suggests an attractive therapeutic opportunity to
protect the tumour suppressors from degradation. We have recently
discovered that E6AP is the major regulator of the stability of the tumour
suppressor PML, by acting as its E3 ubiquitin ligase (Luoria-Hayon
et al., 2009 CDD; Wolyniec et al., 2012, Blood). PML is frequently
downregulated or lost in many cancers; we hypothesize that this is
due to upregulation of E6AP. The overall aim of the PhD candidate
will be to explore the involvement of the E6AP-PML axis in different
human cancers and to test whether restoration of PML by interference
with E6AP, either alone or in combination with chemotherapy and/
or manipulation of PI3K/p53 pathways, is an effective anti-cancer
treatment. The project will involve a variety of molecular and biochemical
assays, as well as cell culture, mouse models and a screen of human
cancer samples.
FAMILIAL CANCER RESEARCH
http://www.petermac.org/research/conducting-research/familial-cancer-research
Head: Dr Gillian Mitchell
Familial cancer research at Peter Mac combines laboratory and clinical research with genetic counselling practice to identify new
hereditary cancer predisposition genes and better identify people with hereditary cancer syndromes, in order to develop new strategies for cancer risk management and personalise cancer treatments. Familial cancer researchers also investigate the wider impact of
these syndromes and their management on the psycho-social well-being of individuals and their families.
LIVING WITH A BRCA1 MUTATION IN THE GREEK COMMUNITY OF
AUSTRALIA
Supervisors: Ms Lucinda Hossack, Dr Laura Forrest and Ms Mary-Anne
Young
Within the Greek population, there are a number of specific BRCA1
mutations which are prevalent in families with hereditary breast and
ovarian cancer. This founder effect is also observed in the Australian
Greek population who receive genetic counselling and testing at familial
cancer centres such as the centre at the Peter MacCallum Cancer
Centre. Inheriting a BRCA1 mutation confers high risks of breast and
ovarian cancer for female carriers. There are many options available
to carriers to manage these risks and increase early detection and/or
prevention of breast and ovarian cancer. Greek Australians who have
a positive family history of breast and ovarian cancer, who choose to
have genetic testing and subsequently learn that they carry a BRCA1
mutation, are encouraged through the genetic counselling process to
talk to their family members about this genetic information.
Communicating genetic information is important to ensure that family
members who are at-risk of also having inherited the BRCA1 mutation
can make a decision about whether they too will pursue genetic testing
to determine their carrier status, informing their cancer risk. For many
Greek Australians, this includes trying to pass information on to family
members who are living in Greece. However, Greek Australians face
various challenges and difficulties when communicating information
about inherited cancer due to cultural taboos surrounding cancer within
the Greek community, the geographical distance between Australia and
Greece, and language barriers. These cultural implications may also
impact the ability of individuals to discuss the outcome of their genetic
test and receive support from their family members. Furthermore,
access to genetic and health services in Greece is limited compounding
the challenges families experience to act on the genetic information.
The aim of this project is to explore the experience of Greek
Australians in learning about their positive BRCA1 carrier status and
communicating this genetic information about BRCA to family members
in Australia and Greece. We are looking for a motivated student who
will undertake qualitative methodology to collect and analyse data
which will be used to ensure Greek Australians are receiving appropriate
support when attending for genetic counselling.
For more information about this project contact:
Dr Laura Forrest, Tel: +61 3 9656 2014; Email: laura.forrest@petermac.
org
For more information about this project contact: Dr. Kamil Wolyniec,
Email: [email protected]; Prof. Ygal Haupt, Tel: +61 3
9656 5871; Email: [email protected]
EXPLORING A NEW REGULATORY PATHWAY OF CELLULAR AGING
(SENESCENCE): IMPLICATION TO CANCER DEVELOPMENT
Supervisors: Dr Christina Gamell, Dr. Kamil Wolyniec, Assoc. Prof. Ygal
Haupt
Published work from our lab and others link E6AP to cell cycle
regulation. Our recent findings revealed a new role for E6AP in the
regulation of cellular senescence and apoptosis. The aim of this project
is to explore these novel regulatory pathways of growth inhibition and
define their involvement in cancer. In this project the PhD candidate
will use a proteomic approach to identify novel regulators of cellular
senescence. The candidate will validate the best hits from this
screen, and characterize their role in the regulation of cell death and
cellular senescence. This project will involve proteomic techniques,
bioinformatic analysis, a variety of molecular and biochemical assays
and cell culture. The candidate will be exposed to work with mouse
models and human cancer samples.
For more information about this project contact: Dr. Cristina Gamell:
[email protected]; Dr. Kamil Wolyniec, Email: kamil.
[email protected]; Prof. Ygal Haupt, Tel: +61 3 9656 5871;
Email: [email protected]
Page 24
2014 Peter Mac Student Projects
Page 25
RESEARCH EDUCATION PROGRAM
http://www.petermac.org/education/laboratory-research-education
The Peter Mac Graduate Research Education program provides excellence in research training and support for all laboratory and
clinician research students as they develop expertise in new technologies, and help drive new discoveries that lead to changes in
research and clinical practice.
Research Education Officer: Dr Caroline Owen; Phone: +61 3 9656 1930; Email: [email protected]
Peter Mac is home to approximately 100 students undertaking
Doctor of Philosophy (PhD), Master of Philiosphy, Doctor of
Medical Science (DMedSci), Master of Surgery and Honours
research programs.
In 2013, the program was formalised to allow students to
develop a record of achievements in their research skills
development during their candidature, incorporating the
following aspects of their development.
The majority of students completing projects at Peter Mac are
enrolled through the University of Melbourne and other Victorian
universities. However, we welcome inquiries from students from
all Universities throughout Australia and overseas.
• Induction and Orientation program
Peter Mac also provides research placements for international
postgraduate students, for undergraduate students associated
with the Summer Vacation Research Program, undergraduate
work experience and Biomedical Science (Pathology major)
research projects undertaken in the laboratories. The Cancer
Research team at Peter Mac also offers opportunities to TAFE
and secondary school students to undertake short-term work
placements in our laboratories.
SEMINAR AND WORKSHOP PROGRAM
The Student Program in conjunction with the Student Society
runs seminars and workshops during the year. The program
for these seminars or workshops is determined in response to
requests and feedback from the student group.
• Hub, Lab meetings & Journal clubs
• The weekly Research Seminar Series provides opportunities
to hear about advances in cancer research at Peter Mac and
external organisations.
• Seminar and workshop programs
• Student Advisory Committee progress reviews
• Staff and students participate in weekly laboratory meetings
and research hub seminars. These seminars provide Peter
Mac researchers with the opportunity to discuss their research
with broad and expert audiences, while also assisting them in
developing presentation and discussion skills and increasing
their breadth of science knowledge and confidence.
• Mentor program
• Peter Mac Student Society and Annual Retreat
• Research and travel support
• Onsite education support
Postgraduate research students based in clinical settings are
supported by the Cancer Research Education program in
addition to the support offered by their clinical service teams.
• Outreach and community activities
The development of a greater awareness of the recent advances
and the rapidly changing technologies used in medical research
is an important aspect of our education program, designed to
has been designed to ensure all students have the opportunity
to expand their knowledge and skills.
The Research Postgraduate Student Society is a student-run
organisation that coordinates educational and social events
for research students throughout the year. The main goal of
the Student Society is to provide a welcoming and supportive
environment for students during their undergraduate and/or
2014 Peter Mac Student Projects
postgraduate studies at Peter Mac. In this regard, the student
society not only supports scientific achievement at Peter
Mac but also builds a strong social and interactive network.
The students organise and facilitate several professional
development workshops to support graduate study, including
a student journal club, technical and career workshops. The
Student Society committee coordinates the annual student
retreat, which serves as a forum for undergraduate and
postgraduate students to discuss scientific ideas, career
opportunities and develop professional skills, as well as allowing
students to interact in a relaxed environment.
PETER MAC POSTGRADUATE STUDENT SOCIETY
Page 26
• We hold professional development seminars and workshops
for our scientists and students, including introductions to
software packages (such as Endnote, Prism and InDesign),
statistics sessions, or career discussions.
• The annual Topics in Cancer Seminar series provides
an opportunity for students and scientists to expand their
understanding of key aspects of cancer research. Each year, a
different theme is developed for this seminar program.
2014 Peter Mac Student Projects
• Community Outreach Research Activities: all students are
encouraged to participate in our range of community outreach
activities, to provide opportunities to gain experience in
communicating their research to a broad range of audiences.
Students are invited to assist with activities including assisting
with school and donor visits and tours, fundraising events,
school visits, Research Open House tours, school and
undergraduate student supervision and mentoring.
FUNDING SUPPORT FOR GRADUATE STUDENTS
Peter Mac has a policy that all graduate research students be
supported by an awarded scholarship. Supervisors and the
Grants team at Peter Mac assist studnets in applying for relvant
scholarships.
All graduate research students at Peter Mac are supported
by $5,000 assigned to support the purchase of a computer,
software and conference travel costs during their research
candidature.
Students apply to access the travel funds for conference and
laboratory research visits during their candidature. Students are
expected to be presenting a poster or oral presentation at the
conference they attend, and to engage in additional activities
(presentations, laboratory visits etc) related to their studies during
their travel in order to gain the most benefit from this trip and
funding support. Students are encouraged to use the travel
funds in the latter part of their candidature, however requests for
earlier travel are considered on a case-by-case basis.
FURTHER INFORMATION:
Research Education Officer: Dr Caroline Owen;
Phone: +61 3 9656 1930;
Email: [email protected]
Page 27
Peter MacCallum Cancer Centre
St Andrews Place, East Melbourne VIC 3002
Phone: (+61 3) 9656 1930
Fax: (+61 3) 9656 1411
Email: research [email protected]
Visit us on the web for information about our research, facilities and our student program:
www.petermac.org/research
http://www.petermac.org/education/laboratory-research-education
2014 Peter Mac Student Projects
Page 28