Study Of C-KIT Mutations In Familial Gastrointestinal Stromal Tumours, Melanoma And A Novel Form Of Waardenburg Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$68,378.00
Summary
The primary aim of this research project is to study mutations in a cancer causing gene called c-KIT. We seek to identify tumour characteristics which are predictive for the presence of particular types of c-KIT mutations in melanomas and gastrointestinal stromal tumours. The detection of tumours harbouring these mutations will help in the treatment of cancer sufferers because this group of patients have been shown to respond very well to a class of drugs known as tyrosine kinase inhibitors.
Mechanisms Of Uptake Of 18F-FDG In An In Vivo Model Of C-kit Induced Neoplasia
Funder
National Health and Medical Research Council
Funding Amount
$438,520.00
Summary
Recent advances in the field of tumour biology have created strong interest in development of molecularly targeted anti-tumour drugs. These targeted drugs are expected to yield higher therapeutic indices with fewer side effects than conventional cytotoxic treatments. However, due to the complicated nature of cellular processes affected by a given treatment, and the high cost of bringing new drugs to the clinic, it is important to define both mechanisms of action and in vivo functional effects of ....Recent advances in the field of tumour biology have created strong interest in development of molecularly targeted anti-tumour drugs. These targeted drugs are expected to yield higher therapeutic indices with fewer side effects than conventional cytotoxic treatments. However, due to the complicated nature of cellular processes affected by a given treatment, and the high cost of bringing new drugs to the clinic, it is important to define both mechanisms of action and in vivo functional effects of targeted therapies early in the drug development process. Gastrointestinal stromal tumour (GIST) is a prime example of a cancer for which a rationally designed drug has been successfully used. GISTs are often associated with activating mutations in c-kit, a gene encoding a cell surface protein. A new drug, Imatinib, inhibits the activity of mutated c-kit and blocks growth of many GISTs. However, over time many GISTs become resistant to Imatinib creating the need to develop additional treatments. Unfortunately, this has been hampered by lack of both a good model system for testing new drugs and robust diagnostic procedures for defining response to treatment. We have now developed a mouse model of GIST that grows and responds to treatment in a similar manner to human GIST. Furthermore, using imaging technology specifically designed for small animal studies, we can quickly monitor and evaluate changes in response during treatment. We propose to use the model system together with small animal imaging technology to define mechanisms by which GISTs respond or become resistant to Imatinib. This involves defining specific molecules within cells that change activity after Imatinib treatment as well as testing a series of gene mutations that may be involved in drug resistance. The results of the study will help to define new targets for GIST treatment as well as validate the imaging strategy that may have wide application to monitoring targeted anti-cancer therapies.Read moreRead less
C-Kit Signalling And Cellular Responses In Haemopoietic Cells
Funder
National Health and Medical Research Council
Funding Amount
$731,115.00
Summary
Growth factors acting on cell surface receptors activate multiple intracellular signalling pathways that regulate cellular growth and function. Mutations in the genes that code for these receptors or their downstream signalling pathways contribute to many human cancers. The contributions of different signalling pathways linked to these receptors to the various cellular responses (growth, maturation, functional activation) are not understood. In this project we aim to use cell and molecular biolo ....Growth factors acting on cell surface receptors activate multiple intracellular signalling pathways that regulate cellular growth and function. Mutations in the genes that code for these receptors or their downstream signalling pathways contribute to many human cancers. The contributions of different signalling pathways linked to these receptors to the various cellular responses (growth, maturation, functional activation) are not understood. In this project we aim to use cell and molecular biology approaches to determine the role of different signalling pathways in cellular responses mediated by the growth factor receptor c-Kit. The c-Kit receptor has essential functions in blood cell development, skin and hair pigmentation, gut function and the reproductive system. It is also essential for the development and function of mast cells which trigger allergic responses such as asthma and eczema. Mutant forms of the receptor have been identified in certain leukaemias and colon cancers. Many new drugs that target specific intracellular signalling pathways have recently been developed and are beginning to be evaluated in clinical trials. Better understanding of how individual pathways contribute to the function of c-Kit and other receptors is essential for optimal use of these new drugs. For example, it may enable the choice of drugs to block c-Kit dependent cancer cell growth or allergic reactions without affecting the growth of normal blood cells.Read moreRead less
Host Determinants Of Hepatitis C-associated Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$610,376.00
Summary
Hepatitis C virus (HCV) infection is a major cause of liver disease and associated deaths in Australia. HCV infection leads to progressive liver failure and may be associated with the development of liver cancer. Currently there are an estimated 220,000 people in Australia living with HCV infection, and by 2020 it is estimated that this number will treble. There is now considerable evidence to indicate that the effect of HCV on the liver is due to ongoing immune activity and the build up of fat ....Hepatitis C virus (HCV) infection is a major cause of liver disease and associated deaths in Australia. HCV infection leads to progressive liver failure and may be associated with the development of liver cancer. Currently there are an estimated 220,000 people in Australia living with HCV infection, and by 2020 it is estimated that this number will treble. There is now considerable evidence to indicate that the effect of HCV on the liver is due to ongoing immune activity and the build up of fat (steatosis) in the liver. This results in the production of biochemical products that lead to tissue damage and to eventual destruction of the liver. Further evidence has recently emerged to suggest that the susceptibility to, and outcome of HCV infection may be influenced by genetic variation in the infected population. The chief investigators on this project have established the best characterised clinical cohort of HCV infected persons worldwide. Further, they have developed considerable expertise in the field of genetics, i.e. the analysis of genes that influence the host's response to an illness. Using this information and expertise, we propose in the present study to analyse in detail the host genetic factors that contribute to variations in the response to HCV, and its correlation with HCV-associated liver damage. This data could allow the development of better patient care strategies and the design of novel therapeutics.Read moreRead less
Evaluation Of Naturally Occurring Resistance To Direct Acting Antiviral Drugs (DAAs) In Individuals With Acute Hepatitis C Infection
Funder
National Health and Medical Research Council
Funding Amount
$333,778.00
Summary
Hepatitis C therapy in the future is likely to involve the use of Directly Acting Antivirals, which offer a better chance of treatment success and shorter treatment courses. The downside to these new agents is the possible development of drug resistance. Studies suggest that drug resistant strains may already exist in some individuals prior to treatment. This study plans to use sensitive methods to examine how common drug resistant strains are in untreated individuals with acute hepatitis C.
The renewal of my Practitioner Fellowship will continue to facilitate an expanding program of epidemiological and clinical research in viral hepatitis, with a primary focus on hepatitis C. New directions will include development of international clinical cohort and trials networks, particularly to characterise the natural history of early hepatitis C infection and evaluate hepatitis C therapuetic strategies for injecting drug users.