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
Targeting Survival Pathways To Overcome The Resistance Of Human Melanoma To Treatment
Funder
National Health and Medical Research Council
Funding Amount
$332,123.00
Summary
Melanoma is a major Australian health problem. This is believed to be due to resistance of melanoma cells to cell death associated with inappropriate activation of survival signalling pathways. My previous studies have provided a number of insights into resistance mechanisms of melanoma cells to apoptosis. I wish to understand more fully the molecular basis of the survival signalling pathways, and to identify new therapeutic targets for overcoming resistance of melanoma to treatment.
Pre-clinical Evaluation Of The LSD1 Inhibitor HCI-2509: Defining The Biomarkers Of Sensitivity And The Mechanisms Of Resistance
Funder
National Health and Medical Research Council
Funding Amount
$340,068.00
Summary
Despite aggressive multi-modal treatment strategies, limited progress in the treatment of Ewing sarcoma (paediatric bone malignancy), has been achieved over the past 30 years. As such, the advent of novel and targeted therapeutics with favourable efficacy/toxicity profiles are eagerly awaited. This proposal will investigate the therapeutic utility of LSD1 inhibition as a treatment for Ewing sarcoma and the underlying mechanisms of sensitivity/resistance to this unique agent.
Discovery And Exploitation Of Novel Biophysical Methods For Charcterising Molecular Pathways Invld In Disease Progression
Funder
National Health and Medical Research Council
Funding Amount
$4,000,000.00
Summary
Dr Cooper has conducted groundbreaking research into the progression and spread of antibiotic-resistant bacterial pathogens. Utilising a strongly multidisciplinary approach, he will use his Fellowship to expand upon this research in the area of antibiotic resistance and will supplement this focus with research into biofilms formed by bacterial pathogens on medical implants, cannulas and catheters. Dr Cooper’s Australia Fellowship will also assist his research into the changes that occur in cells ....Dr Cooper has conducted groundbreaking research into the progression and spread of antibiotic-resistant bacterial pathogens. Utilising a strongly multidisciplinary approach, he will use his Fellowship to expand upon this research in the area of antibiotic resistance and will supplement this focus with research into biofilms formed by bacterial pathogens on medical implants, cannulas and catheters. Dr Cooper’s Australia Fellowship will also assist his research into the changes that occur in cells during the initiation and evolution of cancer.Read moreRead less
Overcoming Resistance Of Human Metastatic Melanoma To Treatment
Funder
National Health and Medical Research Council
Funding Amount
$727,758.00
Summary
Melanoma is a major Australian health problem, but there is no curative treatment once the disease spreads beyond the skin. I have been working on “overcoming resistance of melanoma to treatment” continuously for 10 years. My past research has provided a number of insights into the resistance of melanoma to treatment. I wish to extend my work to find new treatment approaches against the disease. If successful, this work will greatly benefit melanoma patients and Australian people.
Characterisation Of The Anti-apoptotic Function Of P-glycoprotein And Transcriptional Regulation Of The MDR1 Gene.
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
The ability of tumor cells to survive treatment by chemotherapy is a major obstacle in curing patients with cancer. One mechanism by which cancer cells become multidrug resistant (MDR) is their acquired expression of a protein called P-glycoprotein (P-gp) that extrudes cytotoxic drugs out of the cancer cell. We have defined a novel role for P-gp in protecting cells against death induced by non-drug stimuli, where an efflux effect of P-gp would have no obvious benefit. This broader survival effec ....The ability of tumor cells to survive treatment by chemotherapy is a major obstacle in curing patients with cancer. One mechanism by which cancer cells become multidrug resistant (MDR) is their acquired expression of a protein called P-glycoprotein (P-gp) that extrudes cytotoxic drugs out of the cancer cell. We have defined a novel role for P-gp in protecting cells against death induced by non-drug stimuli, where an efflux effect of P-gp would have no obvious benefit. This broader survival effect of P-gp may be explained by its ability to regulate the activity of key enzymes (caspases) that exist within cells to induce cell suicide when appropriate. Many chemotherapeutic drugs activate caspases to kill target cells and as P-gp can inhibit caspase activation, it is therefore possible that P-gp affects the activity of anti-cancer drugs by both removing the drugs from the target cells and inhibiting the pathways through which the drugs can kill a cell. We have mutated P-gp to define the region that is necessary for its caspase regulatory function. We are now identifying the proteins that bind to this region so that we can determine how P-gp regulates caspase activation. In addition, we have defined the manner by which P-gp expression is kept low in normal cells and is upregulated following exposure of cells to chemotherapeutic drugs. The gene encoding P-gp (MDR1) is normally switched off due to the way it is packaged within a nuclear structure called chromatin. We have shown that treatment of cancer cell lines with chemotherapeutic drugs alters chromatin in such a way that the MDR1 gene is activated. We will identify the proteins and complexes involved in drug-mediated regulation of chromatin structure and determine if this phenomenon occurs within patients receiving chemotherapy. Our new findings may lead to novel treatment options for patients that have MDR cancers and may provide insight into possible new ways to inhibit the formation of P-gp-expressing MDR tumors.Read moreRead less
Molecular Basis Of Artemisinin Action And Resistance In Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$758,464.00
Summary
The malaria parasite, P. falciparum causes ~450,000 deaths each year. Resistance to the front-line antimalarial drug, artemisinin, is increasing, threatening at least another 100,000 lives per year, and potentially causing an additional ~A$500M in lost productivity. This project will identify the components of the parasite's cellular defence system that underpin resistance and will point to strategies for overcoming resistance to this important drug class.
Real-time Imaging Of Cell Cycle Progression In Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$526,911.00
Summary
Melanoma is the most aggressive skin cancer and is highly therapy resistant, reasons of which are poorly understood. Here we hypothesise that differences in the growth capacity of melanoma cells in different tumour regions contribute to therapy resistance. We will use a novel microscopic system that allows us to visualise division of individual melanoma cells in intact tumours in real time. Using this system, we will test the effects of targeted therapies on melanoma cell growth and survival.
Targeting The JNK-JUN Pathway To Overcome Therapy Resistance In Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$694,729.00
Summary
Melanoma patients can display remarkable responses to targeted and immunotherapies. However most patients progress rapidly on targeted therapies and only a small proportion respond to immunotherapies. We have found that combination treatment with JNK inhibitors can overcome therapy resistance. We will determine the most efficacious JNK inhibitors available, and the optimal dosing and scheduling of combination treatment for evaluation in patients to improve responses, outcomes and survival.
Roles Of Impaired Apoptosis And Differentiation In Tumourigenesis And Therapy
Funder
National Health and Medical Research Council
Funding Amount
$21,656,910.00
Summary
The ten scientific laboratories in this program have joined forces to investigate two ways in which tumours develop. Both are of particular interest, because they suggest new ways in which cancer might be overcome. Most of our tissues are continually renewed throughout life by production of new cells. Therefore many of the old cells in each tissue must die off to maintain the proper cell numbers. To eliminate cells that are no longer needed or have become damaged, the body has developed a remark ....The ten scientific laboratories in this program have joined forces to investigate two ways in which tumours develop. Both are of particular interest, because they suggest new ways in which cancer might be overcome. Most of our tissues are continually renewed throughout life by production of new cells. Therefore many of the old cells in each tissue must die off to maintain the proper cell numbers. To eliminate cells that are no longer needed or have become damaged, the body has developed a remarkable cell suicide process termed apoptosis. Unfortunately, however, occasionally a random accident to the genes in one of our cells prevents the machinery for apoptosis from being turned on. In that case, the cell will not die when it should and, by continually dividing, it may eventually give rise to a cancer. Since most cancer cells still retain most of the machinery for apoptosis, however, a drug that could switch on this natural cell death machinery would provide a promising new approach to cancer therapy. Identifying and developing such drugs is one major long-term goal of this program. The other focus of our program concerns stem cells. These are rare cells with the remarkable ability to generate an entire tissue. For example, one of our laboratories has identified stem cells that can generate all the cells in the breast. The almost unlimited regenerative capacity of stem cells has a built-in danger. If a stem cell acquires the ability to proliferate excessively, it can go on to form a tumour. Indeed, many cancer researchers now suspect that rare stem cells within a tumour cause its inexorable growth. If tumour growth is maintained by stem cells, it will be essential to develop new forms of therapy that target these rare cancer stem cells rather than merely the bulk of the tumour cells. This is another key long-term goal of our program.Read moreRead less