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This proposal will focus on determining the effect that disruption of molecules involved in repairing DNA has on development of adverse reactions following cancer radiation treatment. Radiation is efective for cancer but tissues that reside next to the tumour are also exposed to radiation (which can damage DNA) during radiotherapy. About 1-5% of radiotherapy patients develop unexpectedly severe side effects in their normal tissues. The dose of radiation used for treatment to the rest of patients ....This proposal will focus on determining the effect that disruption of molecules involved in repairing DNA has on development of adverse reactions following cancer radiation treatment. Radiation is efective for cancer but tissues that reside next to the tumour are also exposed to radiation (which can damage DNA) during radiotherapy. About 1-5% of radiotherapy patients develop unexpectedly severe side effects in their normal tissues. The dose of radiation used for treatment to the rest of patients (>95%) is restrained to assure only a small proportion risk developing severe reactions. If one could predict which individuals were more susceptible to these reactions, then their large dose could be lowered to avoid the problem, and importantly, the dose could be increased for the majority of the patients, which would lead to a higher cancer cure rate. There are over 130 genes involved in repairing DNA. We hypothesize that dysfunctional DNA repair molecules are likely candidates to cause radiosensitivity in these individuals. In fact, a few of these genes have already been found to cause radiosensitivity, but we aim to assess all of the DNA repair genes in samples from patients that have had severe reactions to radiotherapy. Here we will use biospecimens, unique to our study and obtained from clinically radiosensitive cancer patients. We will use very sensitive, state-of-the-art procedures to test RNA and protein levels in our patients' cells and the latest technology to test what happens when candidate DNA repair molecule levels are altered. Additionally, we will determine the changes in DNA repair molecule numbers in response to different doses of radiation. We anticipate that results from these experiments will lead to the development of a clinical assay to test the likelihood of an individual having a severe reaction to radiotherapy, thus allowing individualization of treatment and, reducing radiotherapy side effects ultimately increasing cancer cure rates.Read moreRead less
Function And Regulation Of ATM: Mechanistic Studies
Funder
National Health and Medical Research Council
Funding Amount
$455,250.00
Summary
The human genetic disorder ataxia-telangiectasia is characterised by neurodegeneration, immunodeficiency, radiosensitivity and a very high risk for development of cancer. The gene product defective in this syndrome, ATM, was identified in 1995 and since then its role in protecting the cell against genetic damage has been investigated in some detail. The ATM protein is a very large molecule and to date only one functional region has been described. It is very likely that other regions of the mole ....The human genetic disorder ataxia-telangiectasia is characterised by neurodegeneration, immunodeficiency, radiosensitivity and a very high risk for development of cancer. The gene product defective in this syndrome, ATM, was identified in 1995 and since then its role in protecting the cell against genetic damage has been investigated in some detail. The ATM protein is a very large molecule and to date only one functional region has been described. It is very likely that other regions of the molecule will be important in its function in the cell. This project is designed to investigate the importance of other domains in the protein and also what it is that causes ATM to be activated. We have developed a methodology which allows us to introduce changes anywhere in the ATM gene and then test the effects of these changes in a biological read-cut assay. This approach will enable us to ascribe functional significance to any region of ATM. We will focus on regions where we have some preliminary evidence for activity. Finally we will carry out a mechanistic study to see how ATM is activated. These data will be useful in future design of molecules to interfere with the function of ATM in applications designed to make tumours more receptive to radiotherapy.Read moreRead less
Optimising Synchrotron Microbeam Radiation Therapy For Cancer Treatment
Funder
National Health and Medical Research Council
Funding Amount
$682,000.00
Summary
Over 50% of cancer patients receive radiotherapy (RT). Tumour control using RT is limited by adverse normal tissue reactions. Unlike conventional RT machines, the Australian synchrotron has the capability to deliver strong radiation in very thin slices, termed microbeam RT (MRT). Tumour control has been obtained in animal models with a remarkable sparing of normal tissue using MRT. We will optimize MRT as a crucial step towards a potentially revolutionary cancer treatment.
Role Of Mouse Rad21 And Rec8 Genes In Recombination And Ionising Radiation Response
Funder
National Health and Medical Research Council
Funding Amount
$403,750.00
Summary
We have created a line of mice and are creating a second mouse line which lack two specific genes known as Mrec8 and Mrad21. These genes have a number of roles in mammals. These roles include acting as a glue to hold chromosomes together and allowing exchange of DNA between separate DNA molecules. The latter is important in physiological processes such as genetic exchange during meiosis, but also in the response of the cell to DNA damage, specifically, breakages in both strands of the DNA helix. ....We have created a line of mice and are creating a second mouse line which lack two specific genes known as Mrec8 and Mrad21. These genes have a number of roles in mammals. These roles include acting as a glue to hold chromosomes together and allowing exchange of DNA between separate DNA molecules. The latter is important in physiological processes such as genetic exchange during meiosis, but also in the response of the cell to DNA damage, specifically, breakages in both strands of the DNA helix. In the studies proposed here, we will breed these mice both with each other and with other mice that have specific, single gene defects which lead to abnormal responses to DNA strand breakages. We shall assess the effects of the different genes on response to DNA strand breaking agents in the animals, as well as in cells which have been derived from the animals. These experiments are expected to shed light onto the consequences of defects in DNA repair for the stability of cells and animals, and may provide information which ultimately benefits cancer patients, especially those having radiotherapy.Read moreRead less
A Randomised Trial Of Surgery Versus Surgery Plus Radiotherapy For Regional Control In Patients With Stage 3 Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$305,163.00
Summary
Melanoma is a common disease in Australia. When it has spread to lymph glands it has a poor prognosis. If not controlled it can lead to severe local symptoms including pain, bleeding and disabilty. This is a world first clinical trial involving radiotherapy given after surgery for melanoma involving regional lymph glands. It involves a head to head comparison of surgery alone versus surgery followed by radiotherapy. The target is 230 patients, more than 160 being so far recruited. The main outco ....Melanoma is a common disease in Australia. When it has spread to lymph glands it has a poor prognosis. If not controlled it can lead to severe local symptoms including pain, bleeding and disabilty. This is a world first clinical trial involving radiotherapy given after surgery for melanoma involving regional lymph glands. It involves a head to head comparison of surgery alone versus surgery followed by radiotherapy. The target is 230 patients, more than 160 being so far recruited. The main outcome of the study is control of melanoma in the lymph gland basin. Other outcomes are survival, time to recurrence, side-effects (such as lymphoedema) and quality of life. The trial currently involves 13 centres in Australia, New Zealand and the Netherlands. It is expects to be completed in 2007.Read moreRead less
Functional Significance Of ATM-dependent Phosphorylation Of Mre11
Funder
National Health and Medical Research Council
Funding Amount
$211,500.00
Summary
The aim of the project is to investigate the response of human cells to radiation damage to DNA. Radiation causes double strand breaks in DNA which are responsible for its carcinogenic activity. Several rare syndromes have been described where there is a hypersensitivity to radiation and an increased risk of developing cancer. Cells from these patients have provided a useful means of understanding the basis of sensitivity to radiation and how this may be linked to diseases such as cancer. The in ....The aim of the project is to investigate the response of human cells to radiation damage to DNA. Radiation causes double strand breaks in DNA which are responsible for its carcinogenic activity. Several rare syndromes have been described where there is a hypersensitivity to radiation and an increased risk of developing cancer. Cells from these patients have provided a useful means of understanding the basis of sensitivity to radiation and how this may be linked to diseases such as cancer. The intention here is to investigate some of the normal mechanisms of cellular response to radiation and determine why they are deficient in cells from individuals with these rare syndromes. We will focus on a protein, ATM, which is activated by radiation and on one of its substrates Mre11. Both molecules are involved in sensing and transmitting signals from DNA to cell cycle checkpoints. The expected outcome of this study is a greater understanding of the intricate set of signaling pathways that are activated in response to radiation damage. In addition it is expected that a detailed knowledge of these pathways and what goes wrong in specific disease states will be of assistance in understanding risk of developing cancer. Finally this information will also be useful in the design of novel compounds for the prevention and-or treatment of cancer.Read moreRead less
Analysis Of Low Radiation Dose Outside Of The Treatment Field Received By Cancer Patients Undergoing Radiotherapy
Funder
National Health and Medical Research Council
Funding Amount
$332,384.00
Summary
Every medical intervention is associated with risk. The present proposal aims to quantify the dose from radiation that is delivered outside the actual target region in radiotherapy of breast cancer patients. This information can help the development of better irradiation techniques as well as inform patients and their carers about possible long term side effects. Finally, the research can be used to finetune radiobiological models by comparing clinical outcomes and accurately calculated doses.
Mechanism Of Activation Of ATM By DNA Double Strand Breaks And Other Stimuli
Funder
National Health and Medical Research Council
Funding Amount
$517,751.00
Summary
The human genetic disorder ataxia-telangiectasia is a rare human disease characterised by cancer predisposition and neuronal degeneration. The gene defective in this disorder, ATM, plays a central role in recognising damage to the genetic material and activates a number of different cellular pathways designed to maintain stability of genome and minimise the risk of cancer and other pathologies. In this project we are investigating how the protein is activated from a dormant state to phosphorylat ....The human genetic disorder ataxia-telangiectasia is a rare human disease characterised by cancer predisposition and neuronal degeneration. The gene defective in this disorder, ATM, plays a central role in recognising damage to the genetic material and activates a number of different cellular pathways designed to maintain stability of genome and minimise the risk of cancer and other pathologies. In this project we are investigating how the protein is activated from a dormant state to phosphorylate a series of substrates involved in cellular signaling. Information in this process is very significant since the genetic lesion that activates ATM is a double strand break in DNA which not only is a potentially lethal lesion to the cell but has also the capacity to destabilize the genetic material. Information on this mechanism will also be useful for the design of small molecules that might interfere with ATM activation and in this way make tumour cells more susceptible to radiotherapy.Read moreRead less