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Research Grants Awarded
Identifying Therapeutic Targets by Expression Profiling of DNA Repair in Breast Cancer
Detection, Diagnosis and Prognosis
BACKGROUND: DNA repair genes are involved in the detection, response to and repair of DNA damage. Breast cancer is a malignancy in which faulty DNA repair has been implicated in the pathogenesis in both familial and sporadic cancer. We hypothesise that the knowledge of which DNA repair genes are affected in a tumour can be used to guide the appropriate choice of therapy for breast cancer patients i.e. determining which patients will respond best to which current therapy and which patients might respond to new therapies. OBJECTIVE/HYPOTHESIS: We will use a novel high throughput quantitative RT-PCR methodology that will allow an unprecedented view of the repair status of a breast tumour. We further seek to use this information to choose appropriate DNA damaging therapy to target the tumour. Our underlying hypotheses are • deficiencies in DNA repair occur in many cases of breast cancer • identifying specific DNA repair defects will guide the choice of appropriate therapy. SPECIFIC AIMS: 1. To identify recurrent alterations of DNA repair genes in breast cancer. 2. To identify DNA repair genes that are epigenetically silenced in breast cancer 3. To relate specific repair deficiencies to response to chemotherapy and radiotherapy STUDY DESIGN: This proposal uses the new methodology of low density arrays based on high throughput quantitative RT-PCR to (i) profile DNA repair in cell lines and tumours and (ii) to analyse cell lines for the specific identification of epigenetically silenced DNA repair genes. Finally, model systems will be used to evaluate the therapeutic implications of the repair deficiencies. High throughput quantitative RT-PCR is preferable to microarray analysis because we have found it to have greater reproducibility, dynamic range and low signal to noise ratio. The tumours will be a pathologically well characterised panel from an established Tumour bank.. POTENTIAL OUTCOMES AND BENEFITS OF THE RESEARCH: These studies are targeted towards discoveries that will allow us to improve the appropriateness and effectiveness of DNA damaging therapies in breast cancer. This is the first systematic study of DNA repair gene deficiencies in any cancer. There are major implications for the rational use of chemotherapy and radiotherapy. Knowing which repair pathways are altered can allow us to target tumour cells with specific therapies while leaving normal cells comparatively unscathed.
BACKGROUND: DNA repair genes are involved in the detection, response to and repair of DNA damage. Inactivation of one or more of the many DNA repair genes can lead to an increase in the rate of mutation which hastens cancer development. OBJECTIVE/HYPOTHESIS: Knowing which of the repair enzymes are inactivated in a given tumour will allow us to target that tumour with specific therapies to which the normal cells in the body are relatively resistant. SPECIFIC AIMS: 1. To identify recurrent alterations of DNA repair genes in breast cancer. 2. To identify DNA repair genes that are silenced in breast cancer 3. To relate specific repair deficiencies to response to chemotherapy and radiotherapy STUDY DESIGN: This project aims to identify those tumour-specific repair deficiencies by using a powerful new method that allows us to comprehensively assess the alterations of DNA repair in cancer cells for the first time. This is the first comprehensive study of DNA repair in any cancer. POTENTIAL OUTCOMES AND BENEFITS OF THE RESEARCH: This research is directed towards all breast cancer patients that will receive chemotherapy or radiotherapy both curatively and palliatively. Identifying DNA repair defects will aid the choice of appropriate therapy for breast cancer patients. There are no new risks involved with this approach; rather the risks are with the current approach when patients are assigned to a particular therapy without any knowledge of how the individual patient’s tumour will respond. The results from this study will allow us to choose the most appropriate of existing therapies to target a patient’s tumour. They will also indicate new targets for future therapies.