The Cancer division's groundbreaking research is aimed at improving prevention and treatment strategies and establishing cures for cancers common to many Australians.
Researchers have now identified various molecules that can be targeted in treatment by looking at genomes associated with tumours.
Breast Cancer
The Breast Cancer Research Group is studying the influence of the ovarian steroid hormones, estrogen and progesterone, in the normal breast and in breast cancer.The causes of breast cancer are largely unknown, yet the crucial role of ovarian hormones in normal breast development and function, and their links to breast cancer are undeniable. Large clinical studies of women exposed to progesterone in hormone replacement therapy have unequivocally demonstrated that exposure to progesterone in these formulations increases a woman’s risk of developing breast cancer.
We are investigating the effects of ovarian hormones in normal breast development. Using an innovative three-dimensional model we have developed previously, we are investigating development of the normal breast with treatment regimens mimicking the menstrual cycle. In 2009 we gained valuable knowledge as to how the ovarian hormones individually and in concert regulated normal breast development. Using primary normal tissues and methods optimized in our lab, we are employing high throughput digital immunofluorescent image analysis to investigate the effects of oral contraceptive and hormone replacement formulations on normal breast biology.
Progesterone exerts its effects through the progesterone receptor, which resides in the cell nucleus and, when bound to progesterone, associates with specific sites on chromosomal DNA to regulate expression of specific target genes. We have previously shown that normal progesterone receptor function is dependent on the formation of aggregates between the receptor and important co-factors in the nucleus.
In 2009 we specifically identified one of these key co-regulators, which showed higher expression in cancer cells compared to normal breast cells, suggesting that these co-factors may form abnormal aggregates with the progesterone receptor in cancer. We also utilised a powerful technique that uses high throughput sequencing, across the entire human genome, to predict which genes the progesterone receptor binds to and regulates. We have now identified new target DNAs with which the progesterone receptor interacts, and work is continuing on this analysis to identify further targets, as well as comparing these interactions between normal and breast cancer cells.
Although progesterone is critical in normal breast development, it has since emerged that it is also a major driver of breast cancer risk. Despite this, healthy women are still regularly exposed to synthetic progesterone analogues, such as in the oral contraceptive pill and hormone replacement therapy. Therefore, it is critical that we understand the mechanismsby which progesterone influences breast cancer development so that we can devise strategies to circumvent this increased breast cancer risk.
Breast Cancer Tissue Bank
In 2009 the Breast Cancer Tissue (BCTB) has continued its activity, recruiting donors and collecting and processing specimens from breast cancer patients at BCTB collection centres located across both metropolitan and regional areas of NSW. In addition, a new collection centre based in the ACT began operations and collects from donors in Canberra and South East NSW.
The BCTB headquarters are located within WMI, and management of an extensive clinical and specimen data base is maintained and is being continually enhanced within the WMI facility. Clinical follow up data on donors is also facilitated within WMI.
During 2009 almost 1,000 new donors were recruited to the Bank bringing the total number of donors at the end of the year to over 2,500.
By having actual patient material and data available which has been collected and stored in accordance with world best practice guidelines, the BCTB can support breast cancer research programs across Australia and thus expedite the research effort with the ultimate aim of the translation of research knowledge into clinical practice.
Applications to the BCTB for material and data are subject to scientific scrutiny ensuring the high quality of projects supported. In 2009 a number of applications were received and a total of 2,200 individual specimens were dispatched to research projects across Australia.
For more information visit the Breast Cancer Tissue Bank website.
Melanoma cell cycle research
We now know that cancer is caused by genetic changes, or mutations, in cells. However, the precise sequence of mutations required to transform a dormant melanocyte into a melanoma remains unresolved.
In recent years the group’s work has contributed to the identification of several critical pathways crucial to this process. In particular, the p16INK4a/p14ARF locus, which encodes the tumour suppressor proteins p16INK4a and p14ARF, is altered in 39% of melanoma-prone families and a single base change that activates the BRAF oncogene is found in 50-70% of melanomas. Unexpectedly, this activating BRAF mutation is also found in 80% of benign acquired naevi on sun-exposed skin. High numbers of naevi are associated strongly with melanoma risk but the vast majority of benign naevi never form melanomas, remain arrested for decades and many gradually disappear. Thus, although aberrant activation of BRAF plays a role in melanoma, it also triggers a permanent form of growth arrest, known as senescence, in normal melanocytes.This apparent paradox can be reconciled by the observation that BRAF-induced senescence is bypassed by additional genetic alterations.
The Melanoma Cell Cycle Research Group is investigating the mechanisms responsible for BRAF-induced growth arrest, which is clearly critical in protecting against melanoma formation. In addition, our research will resolve the molecular events that occur during melanoma development and progression.
The team recently confirmed that activated BRAF promotes senescence in human melanocytes. More importantly, they showed that the BRAF-induced protective growth arrest did not require the accumulation of the p14ARF or p16INK4a tumour suppressor proteins. In particular, when p14ARF and p16INK4a expression was silenced in human melanocytes, activated BRAF retained its potent growth inhibitory activity. They also confirmed that the p53 tumour suppressor, which is inactivated in most human cancers, is not necessary for BRAF-induced senescence in melanocytes. These data suggest that additional genes regulate BRAF activity and protect melanocytes from abnormal proliferation and transformation. The group is exploring potential candidate genes that regulate BRAF-induced arrest in human melanocytes.
In recent work secreted factors, such as IL-6 and IGFBP7 have been found to play a significant role in senescence. Our group readdressed the role of IGFBP7 in BRAF induced senescence in human melanocytes. We found no correlation between BRAF mutational status and IGFBP7 expression levels in a series of melanoma cell lines and benign naevi. Furthermore, we found that BRAF potently induced senescence in the presence and absence of IGFBP7. Therefore, the molecules required for BRAF-induced senescence in human melanocytes remain to be defined.
The Melanoma Cell Cycle research team have also shown that accumulation of the p16INK4a tumour suppressor promotes rapid cell cycle arrest that leads to a senescence program characterized by the appearance of DNA foci, activation of acidic ß-galactosidase activity and p53-independence. The team also developed a rapid and accurate functional screen to determine the functional significance of melanoma-associated p16INK4a mutations.The ability to determine variant functional activity accurately would identify disease-associated mutations and facilitate effective genetic counselling of individuals at high risk of melanoma.
The BRAF, p16INK4a and p14ARF molecules are critical in the genesis of melanoma and this research team continues to investigate their functions.This work is essential to the development of a rational approach to targeted therapy for this destructive disease.
Familial Cancer Research group
The Familial Cancer Research Group uses genetic testing to identify individuals at high genetic risk of cancer. In conjunction with this clinical service, many patients are enrolled in collaborative, genetic-epidemiological studies investigating the familial aspects of cancer.
As many high-risk individuals have now been identified, the group established a risk-management clinic in 2006 that facilitates co-ordinated, multidisciplinary care of women at high risk of breast and ovarian cancer, as well as providing further opportunities for research.
Studies done on the molecular profile of ductal lavage fluid from women at high risk are on-going. By 2010, as part of a new research study, most younger (<50) women with a new diagnosis of breast cancer will be offered rapid turn around “treatment focussed” genetic testing. This study has now been approved to start at Westmead. The results will guide cancer management decisions and allow for the appropriate use of the newly developed targeted therapies such as the PARP-inhibitors.
The group continues to participate in the international GOG-199 study, aimed at assessing the usefulness of screening versus preventive surgery in women at increased risk of cancer of the ovary and fallopian tubes. The group has maintained its role in the study of tamoxifen in breast cancer prevention for those at higher risk based on family history (IBIS). As a result of such studies, women at increased risk of breast cancer may choose to takeTamoxifen or Raloxifene to reduce the risk of breast cancer.
Several new studies have been published as a result of collaborations in the investigation of the psychosocial aspects of genetic counselling for cancer susceptibility, including studies the use of telehealth to provide genetic services to rural areas. The group has successfully applied for new funding to extend work already done in developing an on-line tool to assess risk of bowel cancer based on family history of the disease.
Males from families with a genetic predisposition to breast/ ovarian cancer due to germline BRCA1/BRCA2 gene mutations are at increased risk of prostate cancer. The IMPACT study (Identification of Men with a genetic predisposition to ProstAte. CancerTargeted Screening in BRCA1/2 mutation carriers and controls) is evaluating screening in this population. Preliminary results from this study are about to be published in the British Journal of Urology, indicating that these men tend to develop a quite aggressive form of prostate cancer.
The group’s laboratory provides a testing service for individuals in the families described above, primarily for mutations in the BRCA1 and BRCA2 breast cancer susceptibility genes. In addition, there is some testing for susceptibility to melanoma. The laboratory’s research program has been successfully directed towards improved screening for BRCA1 and BRCA2 mutations and continues to focus on improvements to testing and the understanding of the gene mutations (and unclassified variants) that are detected by screening.
Gene expression in cancer
The Gene Expression Laboratory investigates the impact of APC alterations and function in the cell.
By employing sophisticated cell biology and microscopic imaging techniques, they mapped fundamental differences in the cellular location and activity of mutated APC proteins.
In 2009 they pursued new studies that show a link between APC and DNA replication in the cell nucleus, with implications for understanding why some chemotherapy drugs might have reduced activity in APC- mutated colorectal cancers.
In 2009 other protein regulators of colon cancer were also investigated.
In particular, the oncogenic protein beta-catenin was analysed for its movement between the nucleus and cell membrane, and shown to display a rapid turnover at plasma membrane “ruffle” structures involved in cell movement. This work was published and the first to provide a clear analysis of beta-catenin movement in living cells.
This team has also continued their study of the tumour suppressors BRCA1 and BARD1 in breast cancer, and completed new cell imaging studies that characterise the movement of BRCA1/BARD1 to nuclear DNA repair foci and to mitochondria in cancer cells.
Melanoma genomics and genetic Epidemiology
The WICR melanoma genomics and genetic epidemiology group has two major goals. First we want to identify all the genes that most strongly affect melanoma risk, and how that genetic risk interacts with the environment, and we have established a leading role in that filed over many years. More recently we have begun systematically searching for the genes and proteins that make some melanomas more dangerous than others.
In collaboration with the Cell Cycle Research Group we study how these specific genetic changes work to produce melanoma. Our groups are part of a comprehensive research program funded by NHMRC and the Cancer Institute NSW in a multidisciplinary partnership with the clinicians and pathologists of the Sydney Melanoma Unit (now Melanoma Institute Australia), the world’s largest melanoma clinical research centre.
Samples and data from thousands of people with a strong family history of melanoma, who have supported our projects over the last twenty years, have been used to identify new melanoma genes. In addition, our Australian Melanoma Family Study (AMFS), one of the world’s largest population-based studies of melanoma, has studied people who developed melanoma before age 40 in Melbourne, Sydney and Brisbane, or unaffected controls, plus thousands of their family members. Early-onset melanoma can be indicative of increased susceptibility, but little has been known about what genes contribute to risk in this setting.
We have reported in the prestigious journal Nature Genetics two studies that used up to 600,000 DNA markers to compare the genes of people who have had melanoma with those who had not. We identified several genes that make a large contribution to the risk of melanoma in the community; some are involved in skin pigmentation, some in mole development, and others have functions that aren’t yet clear. These genome-wide association studies (GWAS) have involved 22 research groups of the international melanoma genetics consortium (GenoMEL) and several million dollars’ funding support from the European Union and US agencies such as the National Institutes of Health. They have highlighted the contributions WICR researchers are making to melanoma research around the world.
We have gone on to analyse the effect of the environment and lifestyle in the AMFS and have shown that an alarming number of melanomas under 30 can be attributed to the use of sunbeds or solaria.
As part of our CINSW Program we established Australia’s first research clinic for people with a high risk of melanoma in the Sydney Melanoma Diagnostic Centre. It is trialling photographic and other surveillance in a study group of 300 patients whose risk of melanoma is more than ten times the average.
We are showing that new melanomas have been detected early but without excessive removal of non-malignant moles. We have continued to report some of the first research anywhere in the world on perception of melanoma risk and the psychological consequences of high melanoma risk in our melanoma families. These studies have major translational significance and have spun of additional grant support from beyondblue, a national mental health initiative.
We are well advanced in wide-ranging studies of all the genetic and protein abnormalities in melanomas themselves. The goals of this research are to understand how apparently similar melanomas can have such different clinical behaviour, whether a greater propensity to relapse after surgery, or differing responsiveness to drug and biological treatment. These studies are showing that specific mutations, proteins and expressed genes have a strong influence on melanoma outcome and point the way to improved diagnostic tests to support melanoma care, as well as to new targets for melanoma treatment.
Click here for more information including newsletters and forms for projects.
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 cells to ovarian cancer and to improve our understanding of what determines how a patient will respond to chemotherapy.
The Gynaecological Cancer Research Group has continued to work with collaborators on the Australian Ovarian Cancer Study (AOCS), a major national collaborative project involving WICR, the Peter McCallum Cancer Centre (Melbourne), the Queensland Institute for Medical Research (Brisbane) and over 20 cancer treatment centres across the country.
During 2009, in collaboration with Prof David Bowtell and investigators at the Peter Mac, regions of the genome were identified that were specifically amplified or lost in ovarian tumours in association with treatment outcome, for instance the genomic region encoding a central cell cycle gene, Cyclin E, was amplified in women that did not respond to conventional chemotherapy. This work was published in the journal Clinical Cancer Research, and researchers are continuing to work on the mechanisms underlying this effect so that the results can be translated into improved treatment outcomes.
Another major thrust of the Gynaecological Oncology Research Group is the identification of genes and pathways that are involved in the initial steps leading to ovarian cancer and may modify a woman’s risk of developing cancer. In addition to the publication of gene signatures related to ovulation, a major risk factor in ovarian cancer, this work has led to a new pilot grant from the US (Marsha Rivkin Centre for Ovarian Cancer Research) to further examine aberrant gene expression patterns in malignant human ovarian cells and in samples from women at high genetic risk of developing ovarian cancer.
In 2009 the group also participated in an international collaboration led by Dr David Huntsman (British Columbia Cancer Agency, Vancouver) which identified a likely "driver" mutation of the FOXL2 gene in adult-type granulosa-cell tumors, relatively uncommon neoplasms that account for 3 to 5% of all ovarian cancers. This mutation was one of the first identified using whole-transcriptome paired-end RNA sequencing (also called RNA-seq) and was published in the New England Journal of Medicine.
Click here for information on the Gynaecological Oncology Biobank at Westmead.
Leukaemia cell biology
Acute Lymphoblastic Leukaemia (ALL) is the most common childhood cancer and although responsive to chemotherapy, 20% of children and 65% of adults will relapse following treatment. Survival following relapse is poor particularly in adult patients. New treatments for ALL are necessary to improve outcomes for these patients.
ALL cells are highly dependent on the support of other bone marrow cells, generally referred to as stroma, for their growth and survival.These cells also provide protection 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 to enhance currently used therapeutic protocols.
The group has identified a number of stroma-derived factors that modulate ALL cell growth including the cytokines IL-7, VEGF, and PDGF. However the chemokine SDF-1 is the major factor that supports ALL cells. Drugs that can block the effects of SDF-1 mobilize ALL cells into the peripheral blood 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. However, normal bone marrow stem cells are similarly mobilized. We have recently determined that ALL cells remain in the circulation longer than normal stem cells providing a window where the administration of chemotherapy would be expected to produce maximal ALL cell kill with minimal effects on normal cells.
SDF-1 activates a number of molecules within ALL cells. Targeting the p38 MAPK signalling pathway specifically mobilizes ALL cells but not normal haematopoietic stem cells. This has the potential to increase the specificity of current used therapies for ALL cells. Inhibition of p38 MAPK also has direct effects on the proliferation and survival of ALL cells and increases their sensitivity to chemotherapeutic agents. This is at least partially mediated by decreasing the production of supportive factors by the stromal cells.The potential utility of p38 MAPK inhibition as a therapeutic strategy is currently under investigation in pre-clinical models.
The PI-3 kinase pathway is also activated by SDF-1 as well as a number of other supportive factors produced by stromal cells. Disruption of this pathway by blocking a central molecule mTOR results the suppression of growth and induction of cell death in ALL cells.The mechanism of cell death is different from that induced by chemotherapy agents, and as a result, blockade of mTOR enhances the efficacy of chemotherapy in pre-clinical studies of mTOR inhibitors in ALL. A clinical trial of drugs that block mTOR in patients with relapsed acute lymphoblastic leukaemia has now been approved.
Leukaemia cell therapies
The Cell Therapies group focuses on investigating the use of targeted cells for the treatment of infectious and malignant disease in patients with haematological malignancy. In the last three years, the group has been enrolling patients into a gene therapy study in which CMV specificT cells are generated using an adenoviral vector containing the entire CMV pp65 gene.T cells are given to patients after allogeneic stem cell transplantation.
More than 30 patients have receivedT cell infusions from their donors and excellent control of CMV has been observed. The team is now moving to expand the applicability ofT cell infusions to other areas and shortly will introduce infusions that have specificity for a number of other opportunistic infections including EBV andVZV viruses that are common in immunosuppressed individuals.
Immunity to the BK virus that causes bladder and kidney problems in both stem cell and renal transplant recipients is being actively investigated and appears also to be amenable to cell therapy. It is anticipated that clinical trials in these areas will also commence shortly.
Recently, permission was obtained from the National Marrow Donor Program of the USA to utilise stem cell products from American Donors forT cell infusions widening the applicability ofT cell infusions to patients with overseas unrelated donors and simplifying the production process forT cell generation. These advances will enhance the availability to cell therapies to a wide range of immunosuppressed patients.
Translational Oncology
The aim of theTranslational Oncology is to conduct research that is specifically focussed on important clinical issues in oncology, and a major focus of the group is the pathology of breast cancer.
Mammographic screening for breast cancer is an important part of the strategy to reduce the impact from this disease. It has also created a number of challenges in breast pathology reporting. In particular, there are a range of non-cancerous lesions that may give rise to abnormal mammographic appearances prompting investigation by biopsy. This includes a category known as ‘columnar cell lesions’ of the breast or CCLs. While it is clear that CCLs are not themselves malignant, their clinical significance is uncertain and it is important that we learn more about their natural history and any relationship to breast cancer. There have been a number of studies in this area, but progress to date has been hampered by inconsistent nomenclature and classification schemes that make it difficult to directly compare results.
The Translational Oncology group addressed this issue with a study that examined pathologic features of 102 CCLs diagnosed on biopsy following mammographic detection. A systematic analysis approach was applied to determine whether there were natural groupings inherent within the spectrum of screen detected CLLs that might form the basis of a robust classification scheme.
A striking finding from this analysis was that there was extreme variability in the pathologic features of CCLs. However, it was possible to delineate a subgroup consisting of about one third of the 102 cases, that had milder pathologic features and a lower proliferation rate. Using a classification algorithm, this CCL type could be identified in a second series of 32 cases and it was concluded that this classification approach could form a basis for future studies on the nature and significance of CCLs. Results of this study have been published in the journal Pathology (1).