Pathophysiology Of Oxaliplatin-induced Nerve Dysfunction And Neuropathy
Funder
National Health and Medical Research Council
Funding Amount
$281,255.00
Summary
When treating patients diagnosed with cancer, nerve dysfunction is a common complication of chemotherapy, particularly with oxaliplatin. Neurological symptoms develop in up to 90% of patients following oxaliplatin treatment. Neurotoxicity is a key factor in determining the dosage and frequency of current chemotherapeutic agants. Oxaliplatin therapy results in disabling neurological effects. Onset of neuropathy can be relatively fast or in other cases may develop months after therapy has been com ....When treating patients diagnosed with cancer, nerve dysfunction is a common complication of chemotherapy, particularly with oxaliplatin. Neurological symptoms develop in up to 90% of patients following oxaliplatin treatment. Neurotoxicity is a key factor in determining the dosage and frequency of current chemotherapeutic agants. Oxaliplatin therapy results in disabling neurological effects. Onset of neuropathy can be relatively fast or in other cases may develop months after therapy has been completed. The other chief problems encountered during chemotherapy can be overcome: nausea and vomiting can be treated; myelosuppression can be reversed. End organ toxicity such as neuropathy cannot be controlled. Despite the high incidence of neuropathy due to chemotherapy, the mechanisms involved remain poorly understood, particularly with newer therapies. The aim of the present study is to measure nerve function in oncology patients treated with oxaliplatin using a novel protocol, attempting ultimately to identify aspects of dysfunction that correlate with clinical abnormalities, so helping to pin-point the mechanisms responsible for neuropathy. Once identified, management strategies can be developed to better target the prevention and treatment of neuropathy in oncology patients treated with chemotherapy.Read moreRead less
The Trans Tasman Radiation Oncology Group is an experienced research group conducting cancer clinical trials involving radiotherapy (RT) in order to improve cure rates, quality of life and to reduce side-effects of treatment. Fifty per cent of all cancer patients need RT as part of their treatment. The aim of the proposal is to strengthen the quality and safety of RT trials by (a) enabling rapid review and checking of treatment by electronic means and (b) improve trial design.
Cognitive Function And Fatigue In Cancer Patients After Chemotherapy
Funder
National Health and Medical Research Council
Funding Amount
$246,412.00
Summary
Many patients complain of tiredness after chemotherapy and some experience problems with memory, concentration, thinking and other aspects of mental function. Studies have confirmed that some women with breast cancer suffer these effects after chemotherapy and that they can last a long time. Although generally subtle they can affect quality of life and ability to function. Little is known about the causes of these side-effects. Possible causes include blood clotting in small vessels of the brain ....Many patients complain of tiredness after chemotherapy and some experience problems with memory, concentration, thinking and other aspects of mental function. Studies have confirmed that some women with breast cancer suffer these effects after chemotherapy and that they can last a long time. Although generally subtle they can affect quality of life and ability to function. Little is known about the causes of these side-effects. Possible causes include blood clotting in small vessels of the brain and release of molecules called cytokines, as a result of chemotherapy. Hormonal changes and induced menopause might also contribute to these effects in women. Here we propose to evaluate men and women who either receive chemotherapy to prevent recurrence of colorectal cancer, or who are followed without such treatment after surgery. Patients will complete a questionnaire that assesses their level of fatigue and participate in tests of mental functioning, before, during and at intervals after treatment. Possible causes of fatigue and cognitive problems will be studied by measuring products in the blod that indicate blood clotting, levels of cytokine molecules that might cause these symptoms and levels of sex hormones in both men and women. This may lead to further studies to help reduce the burden of fatigue and cognitive impairment from chemotherapy. The goals of our study are to provide comphrehensive information about important side-effects of cancer treatment and to examine the mechanisms that may cause them. This information is important for supporting people living with cancer and for subsequent research to develop interventions that will promote healthy lifestyles during and after treatment for cancer.Read moreRead less
Combined Expression Analysis And SNP-based Measurement Of Copy Number Variation In Ovarian Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$440,124.00
Summary
For a woman with advanced ovarian cancer, the degree and duration of her response to platinum agents is probably the single most important determinant of her chance of survival for an extended period. At the moment we cannot accurately predict that response and, despite a great deal of effort, we don't understand what controls her initial response to treatment and almost inevitable relapse with platinum-refractory disease. In recent years it has become possible to measure the patterns of activit ....For a woman with advanced ovarian cancer, the degree and duration of her response to platinum agents is probably the single most important determinant of her chance of survival for an extended period. At the moment we cannot accurately predict that response and, despite a great deal of effort, we don't understand what controls her initial response to treatment and almost inevitable relapse with platinum-refractory disease. In recent years it has become possible to measure the patterns of activity of thousands of genes simultaneously using microfabricated devices known as microarrays. As aberrant gene activity is a major determinant of tumour growth and drug sensitivity, we expect that such information will provide an insight into the dynamics of tumour growth and lead to tests that are predictive of treatment response and survival. Indeed, there are now a number of examples of solid cancers where microarray-based expression information is predictive of outcome and in breast cancer such information is being actively developed as a clinical tool. Our proposed research is based on the Australian Ovarian Cancer Study (AOCS), which is a national study established in January 2003 through a US Department of Defense CDMRP-OCRP Program grant. In just over 24 months AOCS has become the largest study of its kind in the world and represents a powerful bioresource for the molecular analysis of ovarian cancer. The objective of this application is to extend microarray analysis of AOCS serous ovarian cancer cases, particularly focusing on women with primary and acquired platinum resistance. Platinum resistance is the major barrier to long-term remissions in women with ovarian cancer. High-resolution genomic analysis of a large number of well-selected cases with linked outcome data should provide an extremely valuable molecular dataset for ovarian cancer.Read moreRead less
The Australasian Leukaemia And Lymphoma Group (ALLG) Trial Centre
Funder
National Health and Medical Research Council
Funding Amount
$790,000.00
Summary
Lymphoma, leukaemia and related cancers of the blood affect thousands of Australians, including children. The Australasian Leukaemia and Lymphoma Group, a network of clinical and laboratory haematologists, will integrate laboratory research to discover new approaches to treatment, with clinical trials to test the safety and effectiveness of the new treatments. This approach should accelerate the research and maximise patient and community benefits.
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
Proteomic Screening For Apoptotic Markers In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
The induction of apoptosis, or programmed cell death, is a key factor in the response of tumours to chemotherapeutic agents and ionising radiation; therefore biological markers that predict the clinical outcome to these therapies are needed. Over the past 2 years, our laboratory has developed techniques of protein analysis to evaluate changes in proteins during apoptosis caused by chemotherapeutic agents. Preliminary protein profiling studies of apoptosis induction in human breast cancer cell li ....The induction of apoptosis, or programmed cell death, is a key factor in the response of tumours to chemotherapeutic agents and ionising radiation; therefore biological markers that predict the clinical outcome to these therapies are needed. Over the past 2 years, our laboratory has developed techniques of protein analysis to evaluate changes in proteins during apoptosis caused by chemotherapeutic agents. Preliminary protein profiling studies of apoptosis induction in human breast cancer cell lines showed time-dependent decreases in two proteins, identified as S100A6 and ubiquitin. Both are known to be important in cell function. In the proposed project we will build on our preliminary findings to provide important new information central to the understanding of cancer cell biology and apoptosis in addition to evaluating the ability of anti-cancer treatments to induce apoptosis. Using a combination of protein analysis technologies, this project has the potential to provide reliable and novel biomarkers which will indicate the efficacy and selectivity of anti-cancer treatments in inducing tumour cell death. The knowledge gained in this project will aid clinical assessment of the response to cancer treatment(s) in patients in the form of specific screening assays, and may result in identification and development of effective new agents for cancer treatment and prevention. Furthermore, the outcomes of this project will increase our understanding of fundamental cancer cell biology and apoptosis.Read moreRead less
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
The critical role of the class III histone deacetylase SIRT2 in stabilizing N-Myc oncoprotein. Cancer is the commonest cause of death from disease in children. Neuroblastoma is the commonest solid tumor in early childhood. This project will investigate the critical roles of SIRT2 protein in increasing the expression of N-Myc oncoprotein and consequently inducing neuroblastoma, and SIRT2 inhibitors as anticancer agents.