RESEARCH
PROJECTS
2015
Queen Elizabeth II Medical Centre Unit
School of Medicine and Pharmacology
Address:
Harry
Perkins
Institute
of
Medical
Research
Building,
Block,
Queen
Elizabeth
II
Medical
Centre,
Nedlands
Western
Australia
Postal
Address:
School
of
Medicine
and
Pharmacology
M503,
University
of
Western
Australia,
35
Stirling
Highway,
Crawley
Western
Australia
6009
UWA
School
of
Medicine
&
Pharmacology
–
QEII
Medical
Centre
Unit
RESEARCH PROJECTS 2015
Contents
Introduction
to
the
QEII
Medical
Centre
Unit
–
School
of
Medicine
and
Pharmacology.
...
1
Bone
and
Vascular
Research
Group
...
3
Centre
for
Cell
Therapy
and
Regenerative
Medicine
...
4
Genetic
Epidemiology
&
Molecular
Genetics
...
8
Respiratory
Medicine
...
10
Other
Groups
Offering
Research
Projects
...
14
Nothing is more exciting than making a discovery, or testing your own original
hypothesis. The efficiency of modern research has increased so much that
creative people will find it a fantastic and fast moving career choice.
Professor Barry Marshall
AC
Nobel
Laureate
Introduction to the QEII Medical Centre Unit – School of Medicine and Pharmacology.
The
Queen
Elizabeth
II
Medical
Centre
Unit
(QEII
Unit)
in
the
School
of
Medicine
and
Pharmacology
,
made
up
of
clinicians,
scientists
and
educators,
offers
unique
opportunities
for
students,
scientists
and
doctors
interested
in
pursuing
careers
in
biomedical
research
and
training
across
a
wide
range
of
fields
in
the
health
sciences.
This
booklet
outlines
the
research
and
education
activities
within
the
School
and
with
adjunct
staff
at
SCGH
and
the
opportunities
for
students
and
collaborators
to
work
and
study
within
this
vibrant
group.
Unit
Profile
:
Originally
based
around
clinical
academics,
who
work
for
part
of
their
time
as
medical
specialists
at
SCGH,
and
researchers
and
educators
for
the
rest
of
their
time,
the
SCGH
Unit
has
now
expanded
to
include
a
large
number
of
research
scientists.
The
mix
of
Clinical
Academics,
in
current
clinical
practice,
along
with
highly
trained
and
motived
researchers
from
science
backgrounds
offers
research
opportunities
from
basic
science
through
to
clinical
research,
along
with
intervention,
translational,
epidemiological
and
educational
research
projects.
In
addition,
proximity
to
the
hospital
has
allowed
collaboration
with
adjunct
academics
who
are
active
researchers.
Areas
of
Research:
The
School
offers
opportunities
for
students
to
study
in
many
of
the
disciplinary
areas
in
clinical
practice,
and
researchers
bring
skills
from
the
sciences
to
humanities
and
clinical
practice.
Expertise
in
a
wide
range
of
areas
(statistical,
scientific,
clinical)
can
be
found
within
the
School
or
with
close
collaborators.
SMP
researchers
are
closely
linked
to
research
organisations
and
Universities
sited
locally,
nationally
and
internationally,
including
the
Lung
Institute
of
Western
Australia
(LIWA),
the
Centre
for
Cell
Therapy
and
Regenerative
Medicine
(CCTRM),
the
National
Centre
for
Asbestos
Related
Disorders
(NCARD),
the
Cancer
Council
and
Arthritis
and
Osteoporosis
Western
Australia.
Facilities:
The
SCGH
Unit
is
based
in
the
new
Harry
Perkins
North
Building
on
the
QE11
site,
a
purpose
built
research
facility
developed
by
UWA,
the
Health
Dept
and
the
Harry
Perkins
Research
Institute
of
Medical
Research.
School
researchers
have
access
to
world
class
laboratories
in
an
environment
designed
to
ensure
mixing
of
researchers
and
ideas,
and
sharing
of
equipment,
to
enhance
collaboration
and
success.
Opportunities:
SMP
members
play
a
major
role
in
the
teaching
for
the
professional
practice
Doctorates
with
a
focus
on
the
newly
commenced
Doctor
of
Medicine.
As
is
laid
out
subsequently,
there
are
many
opportunities
to
participate
in
research
in
the
School
through
Honours,
higher
degrees
including
Masters
or
a
PhD,
or
research
projects
which
are
a
required
part
of
the
MD
program.
Funding:
Scholarships
to
cover
student
living
are
available
through
UWA,
the
Unit,
linked
Institutes
such
as
LIWA,
NCARD
and
CCTRM
and
external
bodies
such
as
the
Heart
Foundation
and
the
Asthma
Foundation
Further
Information:
Interested
people
are
encouraged
to
contact
any
individual
academic,
researcher
or
research
group
to
discuss
research
and
funding
opportunities.
Contact
details
for
specific
research
areas
or
projects
are
listed
in
the
following
pages.
You
can
also
contact
the
School
of
Medicine
and
Pharmacology’s
Graduate
Research
Coordinator
to
get
information
related
to
the
specific
area
of
research
and
availability
of
supervision
within
the
proposed
field
of
study
before
lodging
a
formal
application.
Assistant
Professor
Jane
Allan
–
[email protected]
Other useful links:‐
Graduate
Research
Office
–
for
information
about
admission
requirements,
fees
and
the
application
process.
http://www.studyat.uwa.edu.au/research
Scholarship
information
http://www.scholarships.uwa.edu.au/
UWA
International
Office
–
for
overseas
students
considering
postgraduate
research
at
UWA
http://www.studyat.uwa.edu.au/international
Faculty
of
Medicine,
Dentistry
and
Health
Sciences
http://www.meddent.uwa.edu.au/courses/postgraduate
See
what
research
current
Medicine
and
Pharmacology
students
are
undertaking
http://www.medpharm.uwa.edu.au/research/postgraduate
‐
profiles
School
of
Medicine
and
Pharmacology’s
research
programs
http://www.medpharm.uwa.edu.au/research
Research
Projects
–
Bone
and
Vascular
Research
Group
Bone and Vascular Research Group
Project
Title
Meta
‐
analysis
of
effects
of
calcium
and
vitamin
D
on
falls
Supervisor/s
Professor
Richard
Prince
Project
suitable
for
Hons
or
PhD
Outline:
Background: Falling is a major cause of disability as women and men age. The incidence is 30% per year in older women and somewhat less in older men. As a result of the huge expansion in clinical research there are many publications based on controlled trials of interventions to prevent falling. Exercise interventions and nutritional interventions, especially calcium and vitamin D, have been the basis of many studies. To provide overviews or syntheses of these studies in a more objective way the statistical techniques of meta‐analysis have been developed Hypothesis: Specific combinations of calcium and vitamin D reduce falls risk in older individuals.
Techniques and skills:
This project will develop skills of searching the medical data base using search terms. Second it will develop skills of understanding the differences in study design and its implications on outcomes. Next it will develop skills in understanding study implications including outcome assessment. Finally it will develop skills in understanding and implementing the statistical aspects of meta‐analysis. Prerequisites: 1) An interest in understanding the basis of clinical research design and implementation 2) An interest in developing skills in statistical evaluation of research output Outcomes: A publishable scientific paper
Contact
for
further
information
Professor
Richard
Prince
Ph:
61
041
993
7100
[email protected]
Research
Projects
–
Centre
for
Cell
Therapy
and
Regenerative
Medicine
Centre for Cell Therapy and Regenerative Medicine
Project
Title
Elucidating
the
cellular
mechanisms
driving
STAT3
‐
mediated
lung
fibrosis
Supervisor/s
Associate
Professor
Cecilia
Prêle
and
Professor
Steven
Mutsaers
Project
suitable
for
Hons
or
PhD
Outline:
Project description: Idiopathic pulmonary fibrosis (IPF) is a fatal disease of unknown aetiology that is unresponsive to current therapy. It is characterised by excessive deposition of extracellular matrix (ECM) proteins within the pulmonary interstitium, leading to impaired gas transfer, a loss of lung function and death. What drives the development of IPF is unknown but a widely accepted hypothesis is that repeated injury to the epithelium leads to dysregulated healing, initiating a cascade of processes resulting in fibroblast/myofibroblast accumulation and overproduction and deposition of collagen. Our lab has pioneered studies identifying the STAT3 signalling pathway as pivotal in the development of lung fibrosis. The mechanisms regulating STAT3‐mediated fibrosis are unclear, but our preliminary data suggests that STAT3 regulation is impaired in IPF and that STAT3‐mediated effects require epithelial cell and immune cell activation. Hypothesis: STAT3 mediates its pro‐fibrotic effects via epithelial cell activation and altered B cell‐mediated immune regulation. To address this hypothesis, we propose two related, yet independent aims, and each aim constitutes a separate Honours project. Aim 1: STAT3‐induced changes in lung epithelium modulates epithelial cell and fibroblast proliferation, migration, cytokine and chemokine production driving fibrogenesis. Aim 2: B‐cells mediate STAT3‐induced lung fibrosis by regulation of T cell responses. These studies will provide fundamental information on the role of STAT3 signalling pathways in regulating matrix synthesis and may elucidate for the first time effective ways to develop novel therapies to treat patients with IPF. Techniques: Immunohistochemistry, real time PCR, ELISA, Western blot analysis, FACS analysis, confocal laser scanning microscopy, tissue culture, animal models.
Please note that several potential projects exist within this broad programme of research
and we welcome all enquires.
Contact
for
further
information
Associate
Professor
Cecilia
Prele
Ph:
61
8
6151
0958
[email protected]
Project
Title
The
role
of
Bard1
in
pulmonary
fibrosis
Supervisor/s
Professor
Irmgard
Irminger
‐
Finger
and
Associate
Professor
Cecilia
Prêle
Project
suitable
for
Hons
or
PhD
Outline:
This project will be undertaken in a new Centre for Regenerative Medicine in the new state‐of‐the‐art research facility and with a dynamic team who produce high quality publications.
Project description. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with no effective treatment. The pathogenesis of IPF is poorly understood but, TGFβ is recognised to be downstream of key pro‐fibrotic cascades. We have recently discovered evidence suggesting that BRCA1‐associated RING domain1 (BARD1) may be an effector molecule for TGFβ’s actions. It is highly expressed in the fibrotic regions of lungs of patients with IPF, and Bard1 over‐expression in an animal model of lung fibrosis appears to enhance the fibrotic response. BARD1 exists as several isoforms with different functions. Full length (FL) BARD1 is essential for BRCA1 function as an E3 ubiquitin ligase and for apoptosis signalling. However, isoforms lacking the BRCA1‐binding domain have been associated with cancer progression. In particular BARD1β has essential pro‐proliferative functions in mitosis. Altered cellular apoptosis and proliferation are recognised to be central to
Research
Projects
–
Centre
for
Cell
Therapy
and
Regenerative
Medicine
pulmonary fibrosis leading us to investigate the role BARD1 isoforms in the development and progression of this disease. This project will dissect the molecular mechanisms by which BARD1 isoforms contribute to pulmonary fibrosis. Hypothesis: Modulation of BARD1 isoforms by TGFβ is central to the pathogenesis of pulmonary fibrosis. Aim 1: Assess BARD1 expression profiles in various lung cell types and delineate their association with inflammatory or fibrotic forms of IPF.
Aim 2: Determine the role of BARD1 in the development of lung fibrosis in vivo using Bard1
Transgenic and knockout mice.
Aim 3: Dissect the mechanisms by which the TGFβ‐BARD1 axis drives fibrosis.
Techniques: Immunohistochemistry, real time PCR, ELISA, Western blot analysis, FACS analysis, confocal laser scanning microscopy, tissue culture.
Please note that several potential projects exist within this broad programme of research and we welcome all enquires.
Contact
for
further
information
Professor
Irmgard
Irminger
‐
Finger
Ph:
61
8
6151
0957
Irmgard.irminger
‐
[email protected];
[email protected]
Project
Title
Therapeutic
potential
of
combined
chemotherapy
and
targeted
inhibition
of
the
hedgehog
signalling
pathway
in
treating
malignant
mesothelioma
Supervisor/s
Associate
Professor
Cecilia
Prele
and
Professor
Steven
Mutsaers
Project
suitable
for
Hons
or
PhD
Outline:
Project description: Malignant Mesothelioma (MM) is an aggressive asbestos‐associated tumour predominantly of the pleura, with a very poor prognosis. Current treatments are ineffective, therefore novel therapeutic approaches are required. Increasing evidence is pointing to the reactivation and aberrant expression of developmental signalling pathways, such as the hedgehog (Hh) pathway, as critical to the pathogenesis of certain cancers. Blocking this pathway may be a novel therapeutic approach to treat MM. Our laboratory has shown that blocking the Hh pathway using the inhibitor GANT61 inhibits MM cell proliferation and in preliminary studies, GANT61 synergises with the first line MM chemotherapeutic agent cisplatin to induce cell death. Hypothesis: The Hh signalling pathway plays a critical driving role in the pathogenesis of MM and that combined with first line MM chemotherapy, blocking this pathway will be a novel therapeutic approach. Aim 1: Examine the effect of combining GANT61 with first line MM chemotherapeutic agents cisplatin, pemetrexed and gemcitabine on cell death in 2‐D and 3‐D cultures. Aim 2: Examine preclinical efficacy of combining GANT61 with fist line MM chemotherapeutic agents in mouse tumour xenograft models. Techniques: Tissue culture, spheroid cultures, cell transfection, real time PCR, western blot analysis, FACS analysis, cell proliferation, cell viability and apoptosis assays, animal models.
Please note that several potential projects exist within this broad programme of research
and we welcome all enquires.
Contact
for
further
information
Associate
Professor
Cecilia
Pr
ê
le
Ph:
61
8
6151
0957
Research
Projects
–
Centre
for
Cell
Therapy
and
Regenerative
Medicine
Project
Title
Targeting
the
oncogenic
isoforms
of
the
breast
cancer
gene
BARD1
in
melanoma
Supervisor/s
Professor
Irmgard
Irminger
‐
Finger
Project
suitable
for
Hons
or
PhD
Outline:
This project will be undertaken in a new Centre for Regenerative Medicine in the new state‐of‐the‐art research facility and with a dynamic team who produce high quality publications.
Project description: Australia has the highest incidence of melanoma worldwide. Although most melanomas can be detected early and treated successfully, current diagnostic approaches are unable to identify aggressive melanomas that are likely to become invasive and fatal. It is therefore important to identify at risk patients during the early stage of disease pathogenesis. We have recently identified BARD1δ, a differentially spliced form of the tumor suppressor BARD1, as the predominant BARD1 isoform expressed in melanoma. We propose that BARD1δ is a novel melanoma biomarker and a novel target for treatment providing a potential for future targeted therapy to be combined with early detection. BARD1δ is specifically expressed in cancer cells, and its inhibition should therefore not affect healthy cells. Such targeted therapy could be applied locally in cases of melanomas that are too much advanced for surgery or where surgery is difficult or unwanted. Hypothesis: We hypothesise that Bard1δ is novel biomarker and target for the treatment of aggressive melanoma Aim 1. To validate Bard1δ as a biomarker of aggressive melanoma in human melanoma tissue samples Aim 2. To demonstrate that siRNA knockdown of Bard1δ inhibits melanoma cell proliferation in vitro
Aim 3. To demonstrate that repression of Bard1δ inhibits tumor growth in vivo.
Techniques: Immunohistochemistry, real time PCR, ELISA, Western blot analysis, FACS analysis, confocal laser scanning microscopy, tissue culture.
Please note that several potential projects exist within this broad programme of research
and we welcome all enquires
Contact
for
further
information
Professor
Irmgard
Irminger
‐
Finger
Ph:
61
8
6151
0957
Irmgard.irminger
‐
[email protected];
[email protected]
Project
Title
Identifying
IGF
‐
1
as
a
key
driver
of
lung
regeneration
following
pneumonectomy
Supervisor/s
Winthrop
Professor
Geoff
Laurent
and
Associate
Professor
Cecilia
Prêle
Project
suitable
for
Hons
or
PhD
Outline:
This project will be undertaken in a new Centre for Regenerative Medicine in the new state‐of‐the‐art research facility and with a dynamic team who produce high quality publications.
Project description: The capacity for tissue regeneration is highly variable across the species with many amphibians capable of regenerating limbs, tails and even eyes. In humans this capacity is more limited although this varies from one tissue to another. The lung’s regenerative capacity is now recognized to be much more rapid than previously thought even in the adult human. Understanding the mechanisms of this growth and its capacity in human will open up transformational research programmes that may allow us to cure chronic lung diseases that are currently seen as untreatable. Professor Laurent has pioneered studies of lung regeneration and repair following injury. His group has previously shown that IGF‐1 is required for fibroblast proliferation in lung growth of
Research
Projects
–
Centre
for
Cell
Therapy
and
Regenerative
Medicine
rodents post‐pneumonectomy. Furthermore, recent gene expression profile analysis of post‐pneumonectomy lung tissue identified IGF‐1 as a central player although its exact role remains unknown. In this project the role of IGF‐1 in lung regeneration will be determined. Hypothesis: We hypothesize that IGF‐1 is a master regulator in post‐pneumonectomy lung growth and is a key activator of precursor cell differentiation within the lung. Aim 1: To identify the pattern of expression of the IGFIR, IGF‐1 and IGF1BPs in post‐ pneumonectomy and control mouse lung tissue. Archival lung tissue samples collected
from peumonectomised mice will be compared to controls mouse lung tissue.
Aim 2: To demonstrate IGF‐1 knockdown alters repair mechanisms in vitro. The effects of
IGF1 gene overexpression and knockdown will be determined on mouse lung fibroblasts and
epithelial cell proliferation, apoptosis, migration and differentiation.
Techniques: Immunohistochemistry, real time PCR, ELISA, Western blot analysis, FACS analysis, confocal laser scanning microscopy, tissue culture.
Please note that several potential projects exist within this broad programme of research
and we welcome all enquires.
Contact
for
further
information
Associate
Professor
Cecilia
Pr
ê
le
Ph:
61
8
6151
0958
[email protected]
Research
Projects
–Genetic
Epidemiology
&
Molecular
Genetics
Genetic Epidemiology & Molecular Genetics
Project
Title:
Mutations
associated
with
susceptibility
to
polycystic
ovary
syndrome.
Supervisor/s:
A/Prof
Scott
Wilson,
Prof
Bronwyn
Stuckey
Project
suitable
for:
Hons,
MSc
or
PhD
Outline:
Genetic epidemiology and molecular genetics.
Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting up to 10% of women of reproductive age. Despite the high prevalence of the condition, the physiological basis of the disorder is poorly understood. The syndrome is characterized by hyperandrogenism, hirsutism, menstrual irregularities, central obesity and hyperinsulinaemia. PCOS is also commonly associated with the presence of multiple subcapsular follicles and infertility. PCOS is well recognized as a genetic disorder however little progress has been made in revealing the genetic basis of the disorder. In this project the focus will be on the use of next generation sequencing technologies (Exome seq) to identify mutations in relevant genes in families with PCOS. Defining the precise nature of genetic defects that lead to PCOS is crucial for improved diagnosis and for the tailoring of specific therapies for this common condition in young women. Identification of specific gene variants associated with the disease could assist in the specification of lifestyle (e.g. dietary) modifications or particular pharmacological therapies, to aid in PCOS treatment.
Contact
for
further
information
A/Prof
Scott
Wilson
Ph:
61
8
9346
2466
[email protected]
Project
Title
Functional
analysis
of
genomic
copy
number
variants
associated
with
bone
mineral
density.
Supervisor/s
A/Prof
Scott
Wilson,
Prof
John
Walsh
Project
suitable
for
Hons,
MSc
or
PhD
Outline:
Genetic epidemiology and molecular genetics.
Copy number variation (CNV) is a genetic structural phenomenon whereby large DNA sequences, sometimes including functional genes, may be duplicated or deleted in the genome of an individual. The gene copies are thought to be co‐expressed, in which case their presence would result in substantially altered amount of the gene product. Numerous research groups have produced preliminary evidence suggesting the presence of CNV is relevant to complex diseases such as osteoporosis, obesity and neurological diseases. This project focuses on osteoporosis, a heritable, prevalent disease with multiple gene and environmental factors interacting to influence bone fragility fracture susceptibility. This project will address the issue through the in vitro study of cells from subjects that have representative CNV genotypes. This research will validate the effect of the high and low bone mineral density (BMD) associated CNV genotypes on key functional endpoints, including expression of mRNA and protein. A comprehensive understanding of the genetic basis of the disease is vital for improvement in the prevention and treatment of osteoporosis. This study will address this goal by providing knowledge on this important genetic mechanism.
Contact
for
further
information
A/Prof
Scott
Wilson
Ph:
61
8
9346
2466
[email protected]
Research
Projects
–Genetic
Epidemiology
&
Molecular
Genetics
Project
Title
Genetic
basis
of
familial
nonmedullary
thyroid
cancer.
Supervisor/s
Prof
John
Walsh,
A/Prof
Scott
Wilson,
Dr
Vijay
Panicker
Project
suitable
for
Hons,
MSc
or
PhD
Outline:
Cancer and molecular genetics
Thyroid cancer is among the ten most common malignancies, and occurs more often in women than in men. Approximately 80% of all primary thyroid cancers consist of papillary thyroid carcinoma (PTC) and a strong familial association is seen with some types of PTC. The specific identities of the genes involved in familial PTC (FPTC) are as yet unknown. It has been suggested that FPTC is an autosomal dominant condition. In this project DNA from FPTC families will be examined, with ongoing recruitment for additional families. The research will use next generation sequencing (NGS; whole genome or exome), to identify disease‐causing germ‐line single nucleotide variants, insertion, deletions or structural variants in FPTC. DNA samples from affected individuals will be examined in order to identify rare mutations that may play a role in FPTC. The data will then be studied to determine the relevance of rare mutations that are shared by first degree relatives with FPTC. Based on previous work with NGS there is an expectation that mutations in novel genes can be identified from among our study participants. Identification of these rare variants will inform about the underlying cancer biology and will facilitate development of screening tests and ultimately development of a new therapy may be possible.
Contact
for
further
information
A/Prof
Scott
Wilson
Ph:
61
8
9346
2466
[email protected]
Project
Title
Use
of
induced
pluripotent
stem
cells
to
study
pathogenic
gene
mutations
in
familial
thyroid
cancer.
Supervisor/s
A/Prof
Scott
Wilson,
Prof
John
Walsh,
Project
suitable
for
Hons,
MSc
or
PhD
Outline:
Cancer and molecular genetics
Thyroid cancer is the commonest endocrine malignancy, and its incidence has been steadily increasing over the past decade. Causes of thyroid cancer are becoming clearer, for example environmental factors such as ionizing radiation explain some geographic clusters of thyroid cancer. Germline genetic factors are also involved in some thyroid cancers, most obviously in the Mendelian dominant syndromes of familial medullary thyroid cancer (FMTC) and Multiple Endocrine Neoplasia syndrome type 2 (MEN2) which are both associated with germline RET mutations. Outside these syndromes, papillary thyroid carcinoma (PTC) has a particularly high relative risk (8.6‐10.3) in first degree relatives. The genes underlying familial PTC (FPTC) remain largely unknown, but the disease has features of an autosomal dominant disorder and may be monogenic within individual families. Recent studies by our group have highlighted several potential gene mutations involved in FPTC.
In this project induced pluripotent stem cells (iPSCs) derived from somatic cells of study subjects will be used to provide a tool for the study of this disease. iPSC technology enables the epigenetic reprogramming of somatic cells into an embryonic stem cell‐like state followed by differentiation into other relevant cell types. iPSC based model systems will be used to validate and elaborate the functional role of mutations provisionally identified with a role in FPTC.
Contact
for
further
information
A/Prof
Scott
Wilson
Ph:
61
8
9346
2466
[email protected]
Research
Projects
–
Respiratory
Medicine
Respiratory Medicine
Research
Group
Biomarkers
and
Discovery
Unit
Project
Title
Metabolic
acquisition
of
pemetrexed
resistance
in
malignant
mesothelioma
Supervisor/s
Prof
Jenette
Creaney
Project
suitable
for
Hons
or
PhD
Outline:
Malignant mesothelioma is an highly aggressive tumour which is largely resistant to current treatment strategies. Mesothelioma is mainly treated using a combination of two drugs, pemetrexed and cisplatin. However, only approximately a third of mesothelioma patients respond to these drugs and in nearly half of those patients that do initially respond the drugs become less effective over time as the cancer cells evolve to overcome the effects of the drugs. In order to devise strategies to overcome this chemoresistance, we need to know how cancer cells respond to drugs and how the cells change to overcome the drug effects. The proposed project will focus on the drug pemetrexed. Pemetrexed is an anti‐folate, which stops cancer cells dividing by reducing their ability to make the DNA building blocks (i.e. nucleotides) required to make more DNA as the cancer cells multiply. Resistance to pemetrexed is therefore likely to be due to alterations in the cellular pathways that are involved in nucleotide synthesis. We have developed a model system in which mesothelioma cells have, by being exposed to increasing quantities of the drug, become resistant to pemetrexed. In these resistant cells we have preliminary evidence of alterations in some of the cellular pathways involved with nucleotide synthesis. We propose to confirm these observation using independent techniques and extend the findings to other mesothelioma cell models not previously exposed to pemetrexed. Using blood and tumour samples from mesothelioma patients we will determine the clinical relevance of our findings, by comparison with actual patient response to pemetrexed incorporating treatments. If we can identify the cellular pathways that cancer cells use to overcome the effect of pemetrexed, we can then devise additional therapies to target these pathways such that pemetrexed maintains its effectiveness for a longer period of time.
Contact
for
further
information
Prof
Jenette
Creaney
Ph:
61
8
6151
0896
[email protected]
Research
Group
Biomarkers
and
Discovery
Unit
Project
Title
Biological
activity
of
mesothelin
in
malignant
mesothelioma
Supervisor/s
Prof
Jenette
Creaney
Project
suitable
for
Hons
or
PhD
Outline:
Malignant mesothelioma is a highly aggressive tumour which is largely resistant to current treatment strategies. We discovered that patients with mesothelioma have large quantities of a specific protein, mesothelin, present in their blood and pleural effusion. Subsequently the assay for mesothelin has been commercialized and is clinically available for use in mesothelioma diagnosis and monitoring. B The mesothelin protein itself was identified as a mesothelial cell differentiation antigen in 1992, but little is understood about the function or regulation of the protein in normal or malignant mesothelial cells. In this project we will explore the function of the mesothelin using mesothelioma cell lines and various genomic or pharmacokinetic methods to knock‐down mesothelin expression. Preliminary evidence suggests that mesothelin overexpression protects the tumour cell from apoptosis targeting therapies, this will be further explored by testing a range of clinically relevant
chemotherapeutic agents. Results from in vitro studies will be correlated using biospecimens samples from our extensive patient tumour bank.
Contact
for
further
information
Prof
Jenette
Creaney
Ph:
61
8
6151
0896
Research
Projects
–
Respiratory
Medicine
Research
Group
Tumour
Immunology
Group
Project
Title
Identification
of
the
dynamic
cellular
networks
that
underlie
immunotherapy
‐
induced
tumour
regression
Supervisor/s
Asst
Prof
Joost
Lesterhuis,
Prof
Richard
Lake,
Asst
Prof
Scott
Fisher,
Asst
Prof
Andrea
Khong
Project
suitable
for
Hons
Outline:
Background Over the last decades many studies have pinpointed oncogenic events and cellular pathways that initiate or promote thoracic cancer formation and progression. Although compounds targeting these pathways have shown initial promise and effective drugs have been developed, their clinical benefit is often modest. We propose that by focussing on what we do right as clinicians and medical scientists and investigating the molecular and cellular events associated with resolving rather than evolving cancer, we may be able to reinforce or mimic those events to increase the response rates to current treatments. Although in the past, this was not possible because full regressions were not seen in thoracic cancer, recently, immunotherapy with immune checkpoint‐blocking antibodies has shown remarkable success with full cure in a small percentage of patients. We have mirrored this situation in a mouse model, where mice display either full tumour regression or no response whatsoever after immune checkpoint blocking antibodies. Importantly, we are able to sample entire tumours during treatment. This model gives us the unique opportunity to create a comprehensive and detailed map of the molecular network that is associated with therapeutic success. Using a systems biology approach, we identified genetic modules that govern the response to immune checkpoint blockade and we identified drugs that reinforce those response‐associated modules and we could show that these drugs indeed increased therapeutic efficacy. However, we do not know which cell types are responsible for the response‐associated genetic modules. Aim #1 Identify in detail the dynamic, cellular networks that underlie immunotherapy‐induced tumour regression: the student will characterize the cellular constituents (and their phenotype/activation state) of the checkpoint blockade‐induced immune response in the tumour in time during treatment using flow cytometry and immunohistochemistry. Aim #2 The therapeutic relevance for cell types identified in aim 1 will be investigated using depleting or blocking antibodies. These studies will run alongside our systems biology experiments in which we map the molecular networks underlying the response to immune checkpoint blockade, using the same mouse models. This will ensure that the student will be well embedded within the work of the team. Techniques/procedures used Cell culture; immunohistochemistry; flow cytometry; inoculation of tumour cell lines; monitoring of animal welfare and tumour growth; intraperitoneal administration of immune checkpoint‐blocking antibodies. All these techniques are up and running in our lab, although for individual antibody staining optimization may be required. Ethical approval for all mouse studies has been obtained.
We seek a motivated honours student with particular interest in cancer immunology and
animal research.
Please
note
that
several
potential
projects
exist
within
this
broad
programme
of
research
and
we
welcome
all
enquires
