Primary central nervous system (CNS) tumours, arising in the brain and spinal cord, are the leading cause of cancer-related deaths in children less than 15 years of age. Medulloblastomas and other primitive neuroectodermal tumours (PNETs) are the most common form of primary childhood brain tumours, accounting for 25-30% of cases. Despite notable recent advances in our understanding of the molecular genetic basis of malignancies, the pathogenesis of CNS PNETs remains obscure. To address this prob ....Primary central nervous system (CNS) tumours, arising in the brain and spinal cord, are the leading cause of cancer-related deaths in children less than 15 years of age. Medulloblastomas and other primitive neuroectodermal tumours (PNETs) are the most common form of primary childhood brain tumours, accounting for 25-30% of cases. Despite notable recent advances in our understanding of the molecular genetic basis of malignancies, the pathogenesis of CNS PNETs remains obscure. To address this problem, we propose to apply a novel combinatorial approach for the identification of PNET tumour suppressor genes utilising both representational difference analysis (RDA) and microarray expression profiling. Data from this study will help to elucidate the molecular pathways that are compromised in the initiation and growth of PNETs. This information will have direct implications for the development of improved diagnostic and prognostic indicators necessary for the design of more effective therapeutic strategies for the treatment of PNET patients.Read moreRead less
Identification Of Breast And Ovarian Tumour Suppressor Genes On Chromosome 22 By Functional Complementation
Funder
National Health and Medical Research Council
Funding Amount
$249,250.00
Summary
Cancer is fundamentally a genetic disease that arises when errors (mutations) accumulate in genes involved in regulating how and when cells grow. An important class of gene involved in this process are the tumour suppressors whose primary function is to inhibit cell growth. It is widely believed that significant improvements in the treatment and diagnosis of cancer will only be achievable once we have a detailed understanding of how these genes work. It is likely that dozens of tumour suppressor ....Cancer is fundamentally a genetic disease that arises when errors (mutations) accumulate in genes involved in regulating how and when cells grow. An important class of gene involved in this process are the tumour suppressors whose primary function is to inhibit cell growth. It is widely believed that significant improvements in the treatment and diagnosis of cancer will only be achievable once we have a detailed understanding of how these genes work. It is likely that dozens of tumour suppressor genes exist in the human genome and of these only a small proportion have been identified. The aim of this study is to identify genes on human chromosome 22 that are involved in the development of breast and ovarian cancer. Genetic evidence from many investigators, including data from our own laboratory, has indicated that multiple tumour suppressor genes are present on human chromosome 22 but as yet none have been positively identified. Part of the difficulty in identifying these genes is that cancer cells often have a lot of genetic damage and it is hard to distinguish the important changes from background genetic noise'. To circumvent this problem we are using a functional cloning approach which identifies tumour suppressor genes by their ability to inhibit the growth of cancers cells grown in culture in the laboratory. Genes that are identified in this way will be evaluated for the presence of genetic mutations in real human cancers which will give us a better idea of their true significance in tumour development. In addition to enhancing our understanding of the process tumour development this project may identify new targets for anti-cancer therapies.Read moreRead less
Understanding The Molecular Heterogeneity Of Response And Resistance To Anti-HER2-ErbB2 Agents In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$373,173.00
Summary
A revolution in cancer care will take place in the next decade as we aim to individualize treatment for each patient. A subtype of breast cancer relies on a growth factor called HER2 for growth. Treatments that block HER2 are highly effective and have less side effects than chemotherapy. My study aims to further understand of the biology of this subtype of breast cancer and action of anti-HER2 agents as this will allow us to treat this aggressive type of breast cancer more effectively.
Clinical Outcomes In Individuals With An Inherited Predisposition To Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$606,015.00
Summary
Genes have recently been identified which, when abnormal, result in an inherited tendency towards developing breast cancer (BC). It is now possible to undergo testing for abnormalities in these genes. However, there is little known about the best ways to prevent cancer or detect it early in individuals with such a gene abnormality. In addition, it is possible that BCs occuring in women with a gene abnormality might behave differently (have a different prognosis and thus require different treatme ....Genes have recently been identified which, when abnormal, result in an inherited tendency towards developing breast cancer (BC). It is now possible to undergo testing for abnormalities in these genes. However, there is little known about the best ways to prevent cancer or detect it early in individuals with such a gene abnormality. In addition, it is possible that BCs occuring in women with a gene abnormality might behave differently (have a different prognosis and thus require different treatment) from other BCs. Answers to these important questions are essential for women to be able to make informed decisions about how best to reduce their risk of developing, or dying from, BC. This study will examine the clinical outcomes of individuals (both those who have not yet developed cancer and those who have) with an inherited tendency to BC. The study has 2 components; each builds on one of 2 existing Australian studies of hereditary BC 1) Is the likely clinical outcome (prognosis) different for BC patients with a gene abnormality compared to those without? The cancer and treatment details of BC patients in Melbourne and Sydney who are already enrolled in the Australian Breast Cancer Family Study will be examined to determine whether those with a gene abnormality have a better or worse outcome than those without. 2) What factors impact on the clinical outcome (development of cancer) in well individuals with an inherited tendency to BC? An Australia-wide study of inherited BC (kConFab) has recruited families with a strong family history of BC. The family history, lifestyle, exposure to female hormones, cancer screening and preventive surgery details of all individuals in the study will be collected 3 years following study entry. Ultimately this information should help determine how best to prevent cancer in such individuals.Read moreRead less
Defining Steps In The Molecular Pathogenesis Of Lung Cancer Using Immortalized Human Bronchial Epithelial Cells
Funder
National Health and Medical Research Council
Funding Amount
$374,344.00
Summary
Lung cancer remains the leading cause of cancer death worldwide and is caused by abnormalities in DNA. This project aims to further our understanding of this disease by altering known cancer-related genes and studying their effect on lung cancer development. This project also aims to identify novel genes in lung cancer as well as tumour expression profiles which can predict response to chemotherapy agents. In summary, this research will identify new gene targets for therapeutic agents.
Risk Factors, Screening, Prophylaxis And Outcomes In Individuals From Breast Cancer Families: KConFab Follow-Up Study
Funder
National Health and Medical Research Council
Funding Amount
$510,675.00
Summary
Having a strong family history of breast cancer is one of the most important risk factors for the disease. Two major genes, BRCA1 and BRCA2, have been identified which, when abnormal, result in an inherited tendency towards developing breast cancer. Women with a strong family history of breast cancer can undergo testing for these gene abnormalities via Family Cancer Centres around Australia. However, once a gene abnormality is found, little is known about the best ways to prevent cancer or detec ....Having a strong family history of breast cancer is one of the most important risk factors for the disease. Two major genes, BRCA1 and BRCA2, have been identified which, when abnormal, result in an inherited tendency towards developing breast cancer. Women with a strong family history of breast cancer can undergo testing for these gene abnormalities via Family Cancer Centres around Australia. However, once a gene abnormality is found, little is known about the best ways to prevent cancer or detect it early. The Kathleen Cuningham Consortium for Research into Familial Aspects of Breast Cancer (kConFab) has been recruiting families with exceptionally strong histories of breast cancer since 1997. kConFab is funded to collect epidemiological information and biological specimens on such individuals only at the time of their initial recruitment. In 2000 the NHMRC recognised the importance of undertaking clinical follow-up of this precious cohort of individuals, and provided funding through a 3 year project grant to commence the first round of 3 yearly follow-up on this cohort (NHMRC Project Grant #145684). The first 2 years of this follow-up has been completed successfully and the current is application is for a renewal of funding (to commence in 2004) to enable us to undertake further follow-up of the now much larger cohort. In the short term we will examine the screening and preventive surgery behaviours of high risk women within this study to determine whether they are optimal. The ultimate aim of this long term follow-up of individuals in kConFab is to determine what factors impact on the development of cancer in well individuals with a genetic predisposition to breast cancer.Read moreRead less
Molecular Mechanisms And Control Of Alternative Lengthening Of Telomeres
Funder
National Health and Medical Research Council
Funding Amount
$453,055.00
Summary
Studies of a mechanism cancer cells use to protect the ends of their chromosomes The DNA within cell nuclei is arranged in linear packages referred to as chromosomes, capped at each end by structures called telomeres. Telomeres consist of a long stretch of a repetitive DNA sequence that does not contain any genes. Most normal cells are unable to copy the DNA at the extreme ends of their chromosomes, so every time they divide their telomeres get slightly shorter. This ultimately stops the cell fr ....Studies of a mechanism cancer cells use to protect the ends of their chromosomes The DNA within cell nuclei is arranged in linear packages referred to as chromosomes, capped at each end by structures called telomeres. Telomeres consist of a long stretch of a repetitive DNA sequence that does not contain any genes. Most normal cells are unable to copy the DNA at the extreme ends of their chromosomes, so every time they divide their telomeres get slightly shorter. This ultimately stops the cell from dividing any further, and acts as a very potent barrier to the cell becoming cancerous. Some normal cells are not subject to this inexorable telomere shortening: these are the germ cells in the testis and ovary, that are responsible for passing on genetic material to the next generation. Such cells express an enzyme, telomerase, which is able to synthesise new telomeric DNA to replace that lost during cell division. 85% of human cancers are also able to prevent shortening of their telomeres - and thus have breached the barrier that normally prevents unlimited cell proliferation - via telomerase activity. Therefore, if drugs that inhibit telomerase can be developed they may be a very useful new form of cancer treatment. We have found, however, that some cancers are able to prevent telomere shortening by a process that does not involve telomerase, and which we refer to as Alternative Lengthening of Telomeres (ALT). One practical implication of this finding for the design of new cancer treatments is that telomerase inhibitors will need to be used in combination with ALT inhibitors. In this study, we will determine A. how normal cells keep the ALT mechanism permanently shut down and B. the molecular details of the ALT mechanism itself. An understanding of these processes may ultimately contribute to the development of novel cancer treatments that disrupt the ability of cancer cells to divide an unlimited number of times.Read moreRead less
The recent cloning of the breast cancer predisposition gene, BRCA1 had an unexpected consequence. Whereas mutations were found in affected individuals from families showing a predisposition to breast and ovarian cancer, mutations were not identified in breast cancers from individuals with no family history. We have identified a type of change called an epigenetic change affecting BRCA1 in breast and ovarian cancers. Epigenetic changes are mechanisms which act at a gene without causing mutations ....The recent cloning of the breast cancer predisposition gene, BRCA1 had an unexpected consequence. Whereas mutations were found in affected individuals from families showing a predisposition to breast and ovarian cancer, mutations were not identified in breast cancers from individuals with no family history. We have identified a type of change called an epigenetic change affecting BRCA1 in breast and ovarian cancers. Epigenetic changes are mechanisms which act at a gene without causing mutations but nevertheless have the stability of genetic change. We plan to examine breast tumours for further epigenetic changes. This project has important implications for our understanding of the development of breast cancer. This new understanding may in turn suggest new strategies for the treatment of breast cancer.Read moreRead less