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40 41 > Research Report // AR 2006
specific proteins in the cell, with emphasis on cellular
and to improve our understanding of the mechanisms that
clinical outcome and, eventually, improve the survival of
disease in patients with haematological malignancy.
alterations that lead to breast and colon cancer. The group
is investigating how such mutations disrupt the normal
function of the BRCA1 protein.
determine how a patient will respond to chemotherapy.
The normal process of ovulation is known to play a part
in early events leading to ovarian cancer. The Group has
patients with ovarian cancer. In all, more than 1800 patients
have been recruited to the study, surpassing expectations and
data analysis is underway.
In the last 12 months, the group has continued to develop
its clinical program of cytomegalovirus (CMV) specific
cytotoxic T cell administration to patients with impaired
The BRCA1 protein senses DNA damage. It monitors
dividing cells, and in response to DNA damage, initiates
gene repair processes in the cell nucleus so the errors are not
transmitted to new cells. BRCA1 has a partner, BARD1;
their interaction helps facilitate the DNA-repair process.
Previously the group discovered that the BRCA1 and
BARD1 proteins, in their unbound state, are normally free to
shuttle between the nucleus and cytoplasm, but when bound
together they become confined to the nucleus, an essential
step in activating the complexed proteins for their crucial role
in DNA-repair and cell-survival.
They have also identified a class of BRCA1 gene mutations
that display an unexpected influence on the BRCA1 proteins
that carry this mutation. The mutant BRCA1 proteins are
positioned differently inside the cell, and are prevented from
entering the nucleus and complexing with BARD1. This
finding provides another mechanism for changes in DNA
repair elicited by BRCA1 gene mutations in breast cancer.
In 2006 the laboratory discovered that the BARD1 protein
locates at cellular mitochondria, implicating a pathway for
control of cell death or cell survival.
The group is also investigating two genes that appear to
play key roles in colorectal cancer: beta catenin and the
tumour-suppressor gene APC. A very large protein, APC
- like BRCA1 - shuttles between the cytoplasm and the
nucleus, where it performs its tumour-suppressor function.
The ultimate aim of this research is to discover new pathways
that control the action of proteins like BRCA1 and APC
in normal cells, and to develop drugs or other reagents that
correct defects in these pathways in cancer cells.
Gynaecological cancers
Ovarian cancer is the most lethal gynaecological malignancy.
The Gynaecological Cancer Research Group has a program
of research which aims to improve our understanding of the
progression from healthy ovarian epithelial cells to cancer
used laser capture micro-dissection to dissect out individual
epithelial cells from normal ovaries, to studying normal
patterns of gene expression during the ovulatory cycle, using
mice as a model system. They used expression microarrays
to identify all active genes in normal cells, and then use
changing patterns of normal gene expression as a standard to
detect aberrant gene expression patterns in malignant human
ovarian cells. Genes that normally regulate cell proliferation
and apoptosis (programmed cell death) are obvious suspects
for contributing to malignant transformation. The group has
identified several novel candidate genes that may be involved
in the initial steps leading to ovarian cancer.
Most ovarian cancers are initially sensitive to chemotherapy,
but eventually develop resistance. Currently there was no
way to predict which ovarian cancers would become resistant
to chemotherapy, nor any way to modulate gene expression
to restore drug sensitivity. The group has identified a set of
genes whose expression levels differ between resistant and
drug-sensitive cells. They have found that one of these genes
is higher in tumours from patients that have a worse clinical
outcome. The Institute has a patent on the discovery, and is
now seeking compounds to reduce expression of this gene,
that could be used in combination with platinum drugs to
treat ovarian cancer.
The Australian Ovarian Cancer Study is a major
collaborative project involving WICR, the Queensland
Institute of Medical Research (QIMR), and Melbourne’s
Peter McCallum Cancer Centre (PeterMac), and over 20
hospitals across the country. It aimed to recruit 1000 ovarian
cancer patients and create a library of biospecimens at the
PeterMac, for analysis to identify genes involved in ovarian
cancer. QIMR researchers have collected comprehensive
epidemiological data on patients to help identify
environmental and life-style risk factors, while the WICR
group are monitoring the individual patients for a minimum
of five years, recording all details of their treatment and its
outcome. The data will be correlated with risk-factor data
and tumour-gene profiles to identify factors that will predict
Leukaemia cell biology group
The Leukaemia Cell Biology Group is investigating the
role of bone marrow stromal cells in acute lymphoblastic
leukaemia (ALL). ALL is the most common childhood
cancer. Although responsive to chemotherapy 25% of
children and 65% of adults will relapse following treatment
and less than 10% of relapsed patients will survive for 5 years.
New treatments for ALL are necessary to improve outcomes
for these patients.
ALL arises in the bone marrow from cells that normally
develop into B cells (antibody producing cells). ALL cells
are highly dependent on the bone marrow stroma for their
growth and survival and bone marrow stroma protects ALL
cells from the effects of chemotherapy. The leukaemia cell
biology group has been investigating ways in which the bone
marrow supports ALL cells with the aim of disrupting this
supportive and protective function.
The group has identified SDF-1 as a major factor that
supports ALL cells. Drugs that can block the effects of SDF-
1 move ALL cells out of the bone marrow making them
more susceptible to chemotherapy. These drugs inhibit the
growth of ALL cells in the laboratory and in a mouse model
of human leukaemia. These drugs were particularly effective
at minimizing the spread of ALL to other tissues including
the liver and kidney.
The group has also studied the way in which SDF-1
tells ALL cells to grow and survive. By targeting these
mechanisms, even more potent agents have been identified.
It is anticipated that these drugs will enhance the effectiveness
of currently used chemotherapy agents with minimal toxicity.
If successful, these agents will decrease the total dose of
chemotherapy required to treat standard risk patients and
help increase the cure rates in patients with a poor prognosis.
Leukaemia cell therapies
The Cell Therapies group focuses on investigating the use of
targeted cells for the treatment of infectious and malignant
immune systems. The group is currently running its
second clinical trial of CMV specific T cell administration
for patients recovering after allogeneic bone marrow
transplantation. The initial trial using a CMV peptide to
stimulate donor T cells accrued 9 patients. No acute adverse
events were observed and increases in CMV specific T cells
in circulation following infusion were observed. No patient
in the trial required pharmacotherapy for CMV infection or
reactivation.
A considerable amount of effort has been expended in the
last 12 months on gaining approval for a gene therapy trial
of CMV that will expand entry criteria into the trial and will
result in a broader target specificity of CMV antigens. The
trial commenced accrual late in 2006 and has already accrued
8 patients with 4 patients receiving T cell infusions from
their donors. No adverse events have been noted and no
pharmacotherapy for CMV has been required as yet in any
patient receiving T cells.
We are also studying the generation in vitro of T cells
specific for the viral illness varicella zoster that commonly
affect immunocompromised individuals. Using a clinical
vaccine preparation for antigen stimulation, the group has
been able to stimulate growth of a population of T cells
whose specificity is currently being assessed. It is hoped that
this process can be incorporated into generation of CMV
specific T cells to give a tri-virus specific culture product that
will recognise CMV, adenovirus (derived from the vector
encoding the CMV protein pp65) and varicella zoster virus.
Translational oncology
The aim of the Translational Oncology group is to focus
research on clinically important issues in oncology and to
assist clinical application of basic laboratory research through
examination of information and samples from patients with
cancer.
In 2006, the group continued to work to identify measures
that may assist determination of optimal chemotherapy