PhD Opportunities within the
Research Group
Our group has around 20
scientists and uses the latest in technology. We have a strong
program of scientific education, data presentations, visiting
international professors and scientific lab retreats. It is an ideal
environment for PhD research projects.
Main fields of research:
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Tumour Immunology
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Mesothelioma
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Novel clinical trials.
Are you interested? If so, please
contace us.
Tumour Immulology Group,
University Dept of Medicine, Perth.
Discovery
of new tumor antigens
This project is about trying to
identify candidate tumour associated antigens (TAA). These may be
important in three different but related contexts. Firstly and most
obviously the identification of specific antigens may allow the
induction of an immune response to them that can help to clear the
tumour mass. Vaccination as a prophylactic therapy has great appeal,
particularly in mesothelioma where an 'at risk' population is
identifiable. The TAA that are suitable for vaccination may overlap
with TAA that can be used with immunotherapy for patients already
diagnosed with cancer. A third group of antigens which may or may
not overlap will contain TAA that are useful as diagnostic markers
of disease. In this study we propose to determine the relationship
between serological responses to TAA and clinical status.
Contact Richard Lake rlake@cyllene.uwa.edu.au
Successful Cancer Immunotherapy and
Autoimmune Disease
As tumours grow, tumour-specific (neo)
antigens will obviously be co-expressed with a large number of self
antigens. If tumour-specific immunotherapy is successful, it is
likely that self antigens must also be targeted. This raises the
possibility that autoimmune disease will be a consequence of
successful tumour immunotherapy. Using a unique transfection-transgenic
mouse tumour model, this project will evaluate immune responses to
defined tumour antigens in the presence of the same “self”
antigen expressed as a transgene in the pancreas.
Contact Richard Lake rlake@cyllene.uwa.edu.au
Novel
vaccination strategies for cancer
We plan to develop specific immunization protocols in
the animal model of mesothelioma and we anticipate that these
strategies could have a major impact on the focus of therapy in MM
and potentially in other solid cancers. In this context it is
important to note that in some populations the incidence of MM can
approach 20%. These 'at risk' individuals are therefore good
candidates for a preventative vaccination strategy. If we can
develop serological assays for early detection, vaccination could
become an important component of therapy for MM. In this project we
will prepare recombinant vaccinia virus and recombinant
cytomegalovirus expressing MM TAA, identify MHC class I epitopes in
TAA and synthesise polytope DNA vaccines and then undertake
vaccination studies
Contact Richard Lake rlake@cyllene.uwa.edu.au
Development of new cancer gene therapies
It is
very difficult to eradicate tumors once they are established. As we
know the immune system is capable of destroying whole organs during
autoimmune processes, the aim of this study is to try to modify
tumors and the anti-tumor immune response to induce immune
destruction of the tumor in a way that parallels autoimmunity. That
involves overcome the blocks that normally exist to stop autoimmune
destruction. This project involves delivering immunomodulatory
molecules such as IL-12 and GMCSF via gene transfer to animals
bearing tumors, and using other immunomodulatory approaches such as
antiCTLA4 to generate tumor destruction. This work may form the
basis of cancer therapy trials in humans.
In this
project the student could expect to learn how to use animal models
to study diseases, gene delivery techniques, assays of immune
response, flow cytometry, immunoassays, in vitro gene transfection,
PCR, western blotting and immunhistochemistry, at least.
Contact: Prof Bruce Robinson
bwsrobin@cyllene.uwa.edu.au
Viral causes of cancer: SV40 and malignant mesothelioma
Simian virus 40 (SV40) has
attracted increasing attention in recent years as a possible
aetiologic agent in the development of malignant mesothelioma (MM).
A number of studies in Europe and the USA have estimated that
between 44-86% of mesotheliomas carry SV40 like sequences. Others,
however, have not found any indication of SV40 in MM and the area
remains controversial. We will define whether patients with MM
exhibit immunological evidence of exposure to SV40, we will do this
by establishing ELISA assays for determination of antibody responses
to SV40 proteins, measuring T cell responses to SV40, cloning and
sequencing SV40 segments from patients and cell lines and by using
SV40 or its gene products to transform mesothelial cells and
investigating the proximal cellular genetic events.
Contact Richard Lake rlake@cyllene.uwa.edu.au
Dysfunctional Dendritic Cell Interactions in
Anti-tumour Immunity
Studies from our group have demonstrated that
tumour-associated antigens are not simply ignored, but may actually
be presented to and recognised by the immune system. However,
anti-tumour immune response are either weak or rarely generated. We
postulate that poor tumour antigen recognition is largely due to the
failure of a key immunological interaction – that between
antigen-presenting dendritic cells (DC) and antigen-reactive
T cells. This project will utilise a unique transfection-transgenic
mouse tumour model to evaluate the function of DC in the context of
progressively growing tumours and analyse the role these cells play
in presenting tumour associated antigens and priming tumour-specific
T cell responses. Success in these studies could lead to a clear
understanding of the reasons underlying the failure of one the key
interactions in the induction of host anti-tumour responses and may
suggest new avenues for cancer immunotherapy.
Contact: Dr Delia Nelson
delian@cyllene.uwa.edu.au
Development of a spontaneous model of mesothelioma
Mesothelin is a cell surface antigen of unknown function and
is expressed in a highly tissue specific manner. Expression of the
protein is limited to mesothelium, the tissue forming the pleural,
pericardial and peritoneal membranes. The purpose of this study is
therefore to identify and clone elements responsible for the tissue
specific expression of mesothelin. An 1850 bp region of genomic DNA
encompassing the proposed transcriptional start site and 5 UTR has
been cloned. This region lacks a TATA box and other regulatory
elements such as SP1 sites, which are commonly found in promoters.
Transient transfection analysis, demonstrated that mesothelium
specific control elements are present within the 1.85 kb region.
These elements act as a classical enhancer in that they regulate
transcription in an orientation and position independent manner. The
minimal promoter elements occur within a 317 bp region incorporating
70 bp of the 5' UTR. Tissue specific elements are found in the
remainder of the region and are able to activate transcription in a
position and orientation independent manner. Additionlly, a number
of candidate regions have been identified by examination of the
sequence that may bind mesothelium specific trans-acting
factors.
We will define the functional minimal enhancer by making 5' and 3'
deletions of the 1850bp element, define regions of DNase I
hypersensitivity around the gene, demonstrate specificity by gel
shift analysis with oligonucleotides from the candidate regions,
clone mesothelial transcription factors and make transgenic animals
carrying SV40 genes or activated oncogenes under the control of this
promoter
Contact Richard Lake rlake@cyllene.uwa.edu.au
For more details go to the Tumour Immunology
Group page on the School's website at:
http://www.meddent.uwa.edu.au/medicine/groups/
