Every cell in our body has an intrinsic orientation that is controlled by a universal set of genes known as polarity genes. Loss of this orientation is a common and early feature of cancer. We have identified the gene Scribble as a gene that controls cell orientation and is essential to prevent the development of prostate cancer. We propose experiments to discover how Scribble controls prostate cancer and whether it can be used to better predict outcome for prostate cancer patients.
Dissecting PTEN-regulated Pathways In The Genesis Of Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$302,981.00
Summary
Melanoma is a major Australian health problem. It is the third most common cancer in men and women and has a disproportionately heavy impact on productive years of life. The PTEN phosphatase is one of the most common targets for inactivation in melanoma. The precise role of PTEN and its contribution to melanoma development have not been thoroughly explored. This work will highlight potentially novel pathways and molecules that are likely to be critical in the genesis of melanoma and to the ratio ....Melanoma is a major Australian health problem. It is the third most common cancer in men and women and has a disproportionately heavy impact on productive years of life. The PTEN phosphatase is one of the most common targets for inactivation in melanoma. The precise role of PTEN and its contribution to melanoma development have not been thoroughly explored. This work will highlight potentially novel pathways and molecules that are likely to be critical in the genesis of melanoma and to the rational approach to targeted therapy.Read moreRead less
Elucidating The Cellular Processes That Are Critical For P53 Mediated Tumour Suppression
Funder
National Health and Medical Research Council
Funding Amount
$1,016,108.00
Summary
p53 is a tumour suppressor gene that is mutated in ~50% of human cancers. Mutations in p53 cause development of cancer and render malignant cells resistant to chemotherapy. We have identified genes regulated by p53 that appear critical for its tumour suppressive function. In this project, we will use innovative novel genetic tools to discover the cellular and biochemical functions of these genes. The ultimate goal of our studies is to identify novel targets for anti-cancer therapy.
Regulation Of TNF Expression In Inflammation And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$728,447.00
Summary
By studying a spontaneous mutation in mice, we have found an error in the TNF gene (a major factor in many inflammatory diseases) that causes severe arthritis, heart valve disease and gut inflammation. We have also identified new regulators of TNF expression, which might be useful therapeutic targets to limit inflammation. We intend to study the role of these regulators in controlling the expression of TNF, and the link between chronic inflammation and the development of cancer.
Role Of Bcl-2 Family Proteins In The Development And Therapy Of Acute Myeloid Leukaemia (AML)
Funder
National Health and Medical Research Council
Funding Amount
$681,259.00
Summary
Impairment of cell death (apoptosis) is a critical step in cancer development and limits responsiveness to therapy. This project will investigate the influence of several key apoptosis regulators on the development and treatment of acute myeloid leukaemia (AML), a devastating disease with poor prognosis, and explore whether new drugs known as BH3 mimetics can improve treatment.
Investigating Tumour Development And Metastasis Using A Novel Drosophila Cancer Model.
Funder
National Health and Medical Research Council
Funding Amount
$505,500.00
Summary
The majority of cancers are derived from epithelial cells. The primary cause of cancer related deaths is due to the ability of these epithelial cancer cells to migrate and invade other tissues within the body away from their primary tissue of origin (metastasise). This proposal seeks to understand the pathways that are important in regulating the processes of epithelial cell migration and invasion that are instrumental in promoting the metastatic spread of tumour cells. As controls usually opera ....The majority of cancers are derived from epithelial cells. The primary cause of cancer related deaths is due to the ability of these epithelial cancer cells to migrate and invade other tissues within the body away from their primary tissue of origin (metastasise). This proposal seeks to understand the pathways that are important in regulating the processes of epithelial cell migration and invasion that are instrumental in promoting the metastatic spread of tumour cells. As controls usually operate to induce cell death in any cell that attempts to break away and invade other tissues, this proposal also seeks to understand some of the pathways that are responsible for causing these cells to die. To carry out these investigations we have developed a novel Drosophila model of epithelial cancer development. We use this model because of the ease with which it is possible to carry out complex genetic analyses and so dissect the roles of the many different signalling pathways involved in these processes. The strength of the model is that it is dependent upon genetic alterations that are also implicated in the development and metastatic spread of many mammalian cancers, namely activating mutations in two genes, Ras and Notch. It is expected, therefore, to offer considerable insight into why these activated genes also cause the spread of cancer cells in humans.Read moreRead less
Apo2L/TRAIL Killing Of Tumour Cells And The Role Of Inhibitor Of Apoptosis Proteins
Funder
National Health and Medical Research Council
Funding Amount
$390,321.00
Summary
Melanomas and Gliomas are tumour types that respond poorly to current treatments. Current treatments are not only sometimes ineffective, but also unpleasant and may cause co-lateral damage. We will test 2 new targetted anti-cancer treatments, that so far appear to have minor side effects in small animal models, on these difficult to treat tumour types to see if and how they kill them. We also want to know whether these independent treatments can work together to kill tumours more effectively. Al ....Melanomas and Gliomas are tumour types that respond poorly to current treatments. Current treatments are not only sometimes ineffective, but also unpleasant and may cause co-lateral damage. We will test 2 new targetted anti-cancer treatments, that so far appear to have minor side effects in small animal models, on these difficult to treat tumour types to see if and how they kill them. We also want to know whether these independent treatments can work together to kill tumours more effectively. Although we will not personally test these drugs in clinical settings, these drugs or similar are currently in preclinical and clinical trials. This means that understanding how these drugs function is of paramount importance and may result in better clinical trials and possibly more rapid acceptance of the use of these drugs in patients.Read moreRead less
Centrosome Overduplication Contributes To Tumorigenesis
Funder
National Health and Medical Research Council
Funding Amount
$495,010.00
Summary
Cancer can be simplistically thought of as a disease of cell growth and division. In order to improve current treatment regimes and identify new ones, the underlying mechanisms controlling cell proliferation need to be fully understood. By defining these regulatory mechanisms, targets for current chemotherapeutic agents can be further characterised and new ones identified. This will lead to the targeted developments of new classes of drugs which can be used in the fight against cancer.
Role Of Bak And Bax Membrane Anchors In Targeting And Apoptotic Pore Formation.
Funder
National Health and Medical Research Council
Funding Amount
$352,319.00
Summary
In cancer cells the normal process of cell death (called apoptosis) is defective, helping abnormal cells to grow and multiply unchecked. The Bak and Bax proteins are members of the Bcl-2 family of apoptosis regulators, and play a pivotal role in mediating cell death. By defining how these proteins form a pore in mitochondria, the point of no return in cell death, will help the development of novel anti-cancer agents that target the Bcl-2 family in general, and Bak and Bax in particular.
Characterisation Of Cooperation Between Cell Polarity Regulators And Oncogenes In Tumourigenesis Using Drosophila
Funder
National Health and Medical Research Council
Funding Amount
$304,773.00
Summary
Cancers affect 1-3 people at some stage during their lifetime and therefore is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation, cell death or cell movement. In addition, recent studies have shown that the tumour environment (the interaction between cells) can be a major factor in the development of the cancer. However, this is difficult to study in mammalian models. In this proposal we use t ....Cancers affect 1-3 people at some stage during their lifetime and therefore is of major importance to medical science. Cancers arise through the accumulation of mutations that alter normal cell proliferation control, differentiation, cell death or cell movement. In addition, recent studies have shown that the tumour environment (the interaction between cells) can be a major factor in the development of the cancer. However, this is difficult to study in mammalian models. In this proposal we use the genetically amenable, model system, the vinegar fly Drosophila, to investigate the development of tumours using defined mutations. To explore mechanisms of tumourigenesis in Drosophila, we are using a system where we can make patches (clones) of mutant tissue within the context of normal tissue, a system that more faithfully mimics the development of mammalian cancer. We have observed that certain genes required for cell shape, (cell polarity genes, such as scrib) are important in limiting the action of oncogenes (tumour- causing genes, such as activated alleles of Ras) in the development of tumours in Drosophila. Thus, mutants in cell polarity genes cooperate with oncogenic mutations to result in the generation of invasive tumours. In a genetic screen, we have identified further genes that act in a similar manner to cooperate with mutants in scrib or activated Ras. In this proposal we seek to characterise these genes in tumourigenesis and to explore their mechanism of action. The expected outcome of this project is to elucidate novel genes and mechanisms of tumourigenesis in the context of a whole organism. Due to the conservation of cell proliferation and signalling proteins, this proposal is relevant to understanding human cancer.Read moreRead less