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
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.
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
New High-risk Variants For Colorectal Cancer: The Post-GWAS Era
Funder
National Health and Medical Research Council
Funding Amount
$710,105.00
Summary
Our aim is to discover new genes that greatly increase bowel cancer risk. If we can identify these carriers we may be able to prevent them getting cancer. By studying DNA related to bowel cancer, using a novel family design, we will identify families most likely to carry the new genes. We will focus genetic testing, using new techniques, to look for mutations in these prioritised families. Identified mutations will be tested in a 3,500 bowel cancer cases to see how important they are.
Integrating Immunity And Genetics In Follicular Lymphoma To Establish A Prognostic Score Fit For The Modern Era
Funder
National Health and Medical Research Council
Funding Amount
$1,377,174.00
Summary
Follicular lymphoma (FL) is divided into early and advanced stages. Early stage FL is frequently cured, but there is no way to identify who will be cured and who won't. By contrast advanced stage FL is incurable. Our unique access to well-annotated clinical trial and population based cohorts allows us to perform a detailed biological comparison of early and advanced FL, to gain a deeper understanding of the impediments to eradicating the disease, and to predict outcome to conventional therapy.
Regulation Of Cardiometabolic Disease By A Novel ATP Binding Cholesterol Transporter, ABCA8: A New Therapeutic Target?
Funder
National Health and Medical Research Council
Funding Amount
$316,585.00
Summary
Approximately 1.7 million Australians and 12% of the population in Singapore has type 2 diabetes (T2D). We have identified a cholesterol transporter, ABCA8, the absence of which produces symptoms similar to those seen in humans with T2D. The aim of this project is to understand the molecular basis of the diabetes symptoms in mice that do not have ABCA8 with a view to identifying this transporter as a drug target to reduce T2D and its complications, including heart attacks.
Molecular Mechanisms Of Inherited Cardiomyopathies
Funder
National Health and Medical Research Council
Funding Amount
$611,574.00
Summary
Heart failure due to disorders of the heart’s contraction and rhythm is a major health burden for our community. Two of the most common causes of heart failure are dilated cardiomyopathy (DCM) and atrial fibrillation (AF). The broad objective of DF’s research is identification of genetic variants that cause familial forms of DCM and AF, and elucidation of the pathophysiological effects of these variants. A better understanding of disease mechanisms will facilitate new approaches to diagnosis, tr ....Heart failure due to disorders of the heart’s contraction and rhythm is a major health burden for our community. Two of the most common causes of heart failure are dilated cardiomyopathy (DCM) and atrial fibrillation (AF). The broad objective of DF’s research is identification of genetic variants that cause familial forms of DCM and AF, and elucidation of the pathophysiological effects of these variants. A better understanding of disease mechanisms will facilitate new approaches to diagnosis, treatment and prevention.Read moreRead less