Development Of Novel And Selective Anticancer Drugs Derived From Cysteine.
Funder
National Health and Medical Research Council
Funding Amount
$264,250.00
Summary
In the next few years cancer is projected to become the leading cause of death in industrialised countries. Cancer chemotherapy currently relies on destruction of tumours by toxic drugs that indiscriminately kill all cell types, resulting in side effects that limit treatment. In the 21st century new cancer drugs will more effectively destroy malignant tumour cells without damaging normal cells. The R and D herein will value-add to our discovery of a new class of potent and orally active anti-tum ....In the next few years cancer is projected to become the leading cause of death in industrialised countries. Cancer chemotherapy currently relies on destruction of tumours by toxic drugs that indiscriminately kill all cell types, resulting in side effects that limit treatment. In the 21st century new cancer drugs will more effectively destroy malignant tumour cells without damaging normal cells. The R and D herein will value-add to our discovery of a new class of potent and orally active anti-tumour drugs that possess unusually high selectivity in acting on cancer cells without killing normal human cells. Our current proof of concept will be turned into a drug development candidate that will improve our negotiating position with commercial partners.Read moreRead less
OVERCOMING RESISTANCE OF HUMAN MELANOMA TO CHEMOTHERAPY
Funder
National Health and Medical Research Council
Funding Amount
$499,500.00
Summary
Melanoma is the third most common cancer in women and men respectively. In NSW alone approximately 400 die each year from the disease. The main treatment of melanoma is surgical removal of the primary tumor on the skin but once the disease spreads beyond the skin to other organs there is no curative treatment. This study will identify whether resistance of melanoma to chemotherapy is due to failure to induce sufficient levles of pro-apoptotic BH3 only proteins and-or activation of apoptosis resi ....Melanoma is the third most common cancer in women and men respectively. In NSW alone approximately 400 die each year from the disease. The main treatment of melanoma is surgical removal of the primary tumor on the skin but once the disease spreads beyond the skin to other organs there is no curative treatment. This study will identify whether resistance of melanoma to chemotherapy is due to failure to induce sufficient levles of pro-apoptotic BH3 only proteins and-or activation of apoptosis resistance pathways. The results will be directly relevant to subsequent clinical trials in melanoma paients. Apoptosis may be triggered by chemotherapeutic agents but human melanoma shows wide variability in apoptotic responses to chemotherapy. Recent studies have shown that the Bcl-2 family of pro- and anti-apoptotic proteins and inhibitor of apoptosis proteins appear to be key regulators of the (mitochondrial) apoptosis pathway induced by chemotherapy. The activity of the proteins appear to be regulated by several signal pathways in the cell which may be activated by signals external or intrinsic to the cell. We wish to characterize the proteins involved in chemotherapy induced apoptosis, assess their variability between melanoma cells that are sensitive or resistant to apoptosis and characterize the signal pathways involved in regulating the proteins in human melanoma.Read moreRead less
Molecular Determinants Of Risk, Progression And Treatment Response In Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$8,381,820.00
Summary
Melanoma is a major Australian health problem. NSW figures for 2002 show it to be the second most common cancer in men and women. It has a disproportionately heavy impact on productive years of the life of young Australians because it is the commonest cancer in those aged 15-45 years. The investigators are all associated with the Sydney Melanoma Unit (SMU), the world�s largest clinical service dedicated to the treatment of melanoma, treating >1200 new melanoma patients annually. We have also ....Melanoma is a major Australian health problem. NSW figures for 2002 show it to be the second most common cancer in men and women. It has a disproportionately heavy impact on productive years of the life of young Australians because it is the commonest cancer in those aged 15-45 years. The investigators are all associated with the Sydney Melanoma Unit (SMU), the world�s largest clinical service dedicated to the treatment of melanoma, treating >1200 new melanoma patients annually. We have also recruited large cohorts of individuals with high susceptibility to melanoma, both familial and population-based, throughout southeastern Australia. We aim to utilise these unique, internationally-recognised resources to develop a scientific basis for 1) improved management of individuals at high risk for development and progression of melanoma, and 2) improved treatment of patients with early and disseminated melanoma. We will base this on consolidation of existing collaborative research into molecular predictors of risk, progression and treatment response in melanoma.Read moreRead less
THE REGULATORY MECHANISM OF HAEM OXYGENASE PROTECTION AGAINST PHOTOIMMUNOSUPPRESSION AND SKIN CANCER
Funder
National Health and Medical Research Council
Funding Amount
$439,500.00
Summary
Current dogma holds that UVA radiation adds to UVB damage in the skin. However we have identified a window of UVA doses, easily achievable from daytime sunlight exposure, that do not cause sunburn and are not immunosuppressive, but that significantly attenuate the damaging effects of UVB. In mice the mechanism partially depends on the UVA-upregulated cytokine interferon-gamma, and strongly on the UVA-inducible antioxidant enzyme haem oxygenase-1 (HO-1). This project aims to establish how the HO- ....Current dogma holds that UVA radiation adds to UVB damage in the skin. However we have identified a window of UVA doses, easily achievable from daytime sunlight exposure, that do not cause sunburn and are not immunosuppressive, but that significantly attenuate the damaging effects of UVB. In mice the mechanism partially depends on the UVA-upregulated cytokine interferon-gamma, and strongly on the UVA-inducible antioxidant enzyme haem oxygenase-1 (HO-1). This project aims to establish how the HO-1 gene is regulated by UVA. Available data from cultured human skin cells suggest that HO-1 is UVA-inducible in fibroblasts but not keratinocytes, whereas we found both cell types respond in mouse skin, keratinocytes most actively. We will ascertain whether a species difference, or an anomaly in cultured cells, underlies these discrepancies. With human skin grafted onto immunodeficient SCID mice, we will study impaired immune function, an important prerequisite for cancer, compared with mouse skin in vivo. Using molecular biology techniques with this model, we will monitor the activity of the transcription factor Bach 1, known to bind to the DNA of the HO-1 promoter region to repress the gene normally, but reversibly by haem-binding, and the corresponding activity of HO-1, during immunoprotective (UVA exposure, haem elevated) conditions. Immunoprotection may result from binding by Bach 1 of haem released from microsomal proteins by UVA, its release from DNA and thus derepression of HO-1. We will seek evidence of a role for skin cytokines in modifying Bach 1 binding, and for Bach 1 and HO-1 actions during photocarcinogenesis induction with chronic UV exposure. The significance of the outcome of the studies will be in understanding how a natural ameliorating pathway induced by UVA radiation could be utilised for superior photoprotection strategies for skin cancer susceptible humans.Read moreRead less
The Role Of Protein Tyrosine Phosphatases Regulating Eph RTK-signalling And Modulating Invasive Tumour Cell Properties.
Funder
National Health and Medical Research Council
Funding Amount
$303,828.00
Summary
The Ephs and interacting ephrins are proteins on the cell surface, which enable orientation of cells that move within the body tissues and organs, but also in tumours. Eph proteins have tyrosine kinase enzyme activity that becomes active after binding ephrins on neighbouring cells. Once active, they instruct these cells to change their shape and their adhesion to the substratum or between each other, and to become more motile. In adult organisms Ephs and ephrins are low in most cells, but they r ....The Ephs and interacting ephrins are proteins on the cell surface, which enable orientation of cells that move within the body tissues and organs, but also in tumours. Eph proteins have tyrosine kinase enzyme activity that becomes active after binding ephrins on neighbouring cells. Once active, they instruct these cells to change their shape and their adhesion to the substratum or between each other, and to become more motile. In adult organisms Ephs and ephrins are low in most cells, but they re-appear in many tumors. For example, when normal cells in the skin (melanocytes) become tumor cells, they often will have Ephs and ephrins on their surface. It is believed that these proteins will now affect if these melanoma cells will migrate and to which locations within the body. In our studies we will examine what controls the activity of Eph proteins. In particular, a class of enzymes called tyrosine phosphatases are known to regulate the function of tyrosine kinase receptors, however it is not clear which particular phosphatase regulates EphA3, the focus of our studies. We will find out, which set of phosphatases regulates EphA3 function and whether exposure to oxidative conditions, such as UV radiation, also activates Ephs and instructs tumour cells to become more motile and to invade other areas of the body. The understanding of this mechanism will help to understand the cause of cancers such as melanoma and might offer possibilities to optimise new strategies for its treatment.Read moreRead less
EphA3-modulated Cell Positioning In Tumour Invasion And Neovascularisation.
Funder
National Health and Medical Research Council
Funding Amount
$647,232.00
Summary
During the progression of human cancers, tumor cells increasingly lose their ability to communicate and co-exist in a regulated fashion with normal cells to maintain the status quo. Because they multiply uncontrollably, tumour cells spread into surrounding tissue and can invade other organs of the body. The Ephs and interacting ephrins are proteins on the cell surface, and their communication controls the position of cells within the body tissues and organs, but also in tumours. Together with co ....During the progression of human cancers, tumor cells increasingly lose their ability to communicate and co-exist in a regulated fashion with normal cells to maintain the status quo. Because they multiply uncontrollably, tumour cells spread into surrounding tissue and can invade other organs of the body. The Ephs and interacting ephrins are proteins on the cell surface, and their communication controls the position of cells within the body tissues and organs, but also in tumours. Together with collaborators at the Ludwig Institute for Cancer Research and the Queensland Institute for Medical Research we produced two proteins, an antibody and a recombinant ephrin that bind one of the Eph proteins on tumour cells. The antibody allowed us to locate Eph in tumours, where it appears surprisingly not only on tumour cells but also on tumour blood vessels. When attached to a redioactive compund it selectively targets the cancer cells and in an animal study prolonged the survival of mice with leukemia significantly. We will now investigate the exact role of this Eph protein in tumour blood vessels. We will then study what happens in tumours when a toxic antibody-drug compound targets this tumour and starts to kill tumour cells. Finally, we will devise a novel reagent that combines the properties of the antibody with the properties of the ephrin into a single protein, which can deliver a cell-killing drug exclusively and most efficiently to tumour cells containing the Eph protein on its surface.Read moreRead less