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    Research Grants Awarded

    Targeting DNA Repair Deficienies In Human Breast Cancer

    Grant Mechanism:
    Investigator Initiated Research

    Scientific Abstract:
    Individualization of cancer therapy is a major goal for the 21st century. The use of neoadjuvant therapy allows the opportunity to observe the response of human tumors in vivo, and the goal of this study is to develop a biological function-based predictor of the response to therapy. Cisplatinum and radiation are a potent combination for a number of squamous carcinomas, but is not used routinely in the treatment of breast cancer. Cisplatinum acts by inducing both intra- and inter-strand crosslinks, and radiation induces both single and double strand breaks. The combination of platinum and radiation produces complex lesions that are potent blocks of the replication fork, and the only recovery pathway is to use homologous recombinational repair. The hypothesis generated by these observations is that tumor cells that are defective in this pathway of DNA repair, involving BRCA1 and BRCA2, should be sensitive to this therapy. The idea is supported by cell survival assays in culture. The central plan of this project is to measure DNA repair directly in breast cancer cells, by ex-vivo irradiation of the breast cancer cells directly after fine needle aspiration. The clinical study enrolls women with T3 or T4 triple-negative breast cancer, with a primary tumor or nodal disease site that can be evaluated for response. Patients will receive neoadjuvant chemo-radiation therapy, using single agent cisplatinum 25 mg/m2 every week during the 6 weeks of radiation therapy (50-60 Gy in 1.8-2.0 Gy per fraction), followed by 3-weekly platinum at 75 mg/m2 at weeks 7 and 10. The response of the tumor will be analyzed by pre-operative imaging and surgical evaluation of residual disease at the time of mastectomy. The effect of DNA repair status will be analyzed in relation to the response rate of the tumors. The results will determine whether individualization of therapy based on functional analysis of DNA repair is a valuable addition to improving the effectiveness of therapy. Pre-clinical studies will explore novel combinations of therapy designed to exploit the defect in DNA repair, by combining platinum and etoposide, radiation and PARP inhibitors, and the additional effect of inhibiting the ?salvage? pathway of DNA repair involving Rad52. The ultimate goal is that these novel strategies will lead to highly effective therapies for triple-negative tumors with a DNA repair defect in homologous recombination.

    Lay Abstract:
    Individualization of cancer therapy is one of the major goals for cancer research in the 21st century. The use of neoadjuvant therapy allows the opportunity to observe the response of human tumors in vivo, and therefore allow the opportunity to customize the effectiveness of therapy. The goal of this research proposal is to identify an important characteristic of human breast cancer, a defect in its ability to repair DNA damage by a specific mechanism, involving the BRCA1 and BRCA2 proteins, that is used to repair damage from specific type of cytotoxic therapies. Therefore, the initial goal is to develop a novel type of biomarker in breast cancer ? a function-based marker which reflects the integrity of the DNA repair pathway called homologous recombination. The advantage of using a functional assay is that it should capture all of the tumors that show the key phenotype, regardless of the mechanism. There are many potential ways to inactivate the ?BRCA-pathway? ? the development of a functional assay should capture all mechanisms, known and to be discovered. Cisplatinum and radiation have been used as a potent combination for a number of human cancers, but is not used routinely in the treatment of breast cancer. Cisplatinum acts by inducing both intra- and inter-strand crosslinks, and radiation induces both single and double strand breaks. The combination of platinum and radiation produces complex lesions that are potent blocks of the replication fork, and the only recovery pathway is to use this BRCA-pathway of homologous recombinational repair. The hypothesis generated by these observations is that tumor cells that are defective in this pathway of DNA repair should be sensitive to this therapy, and this idea has been supported by cell survival assays in culture. The clinical trial is designed to answer this question. Finally, preclinical studies will proceed in parallel with the clinical trial to optimize the best combination of cytotoxic therapies and biological manipulations. The results will determine whether individualization of therapy based on functional analysis of DNA repair is a valuable addition to improving the effectiveness of therapy in triple-negative breast cancer.