Epithelial ovarian cancer (EOC) is the fourth leading cause of cancer-related death in women in the United States and is the leading cause of gynecologic cancer death. A major limitation in the treatment of ovarian cancer is the widespread development of resistance to a broad range of chemotherapeutic agents. This is confounded by the lack of means to rapidly detect chemo-response. The induction of apoptosis is one of the key mechanisms by which chemotherapeutic agents exert their cytotoxicity. This proposal is based on the hypothesis that therapeutic modulation of the factors that induce or block apoptosis may represent a specific approach for ovarian cancer therapy. In addition, we hypothesize that downstream products of the apoptotic cascade can be detected and measured in the serum of patients and may serve as markers for chemo- response. The main objectives of this proposal are: 1) to further enhance our understanding of the main regulatory factors of apoptosis in ovarian cancer cells, and 2) to develop a means to rapidly monitor response to treatment. Specifically we propose:
Aim 1. To determine the regulators and effectors of caspase-2 in the process of chemo-response in EOC cells;
Aim 2. To determine the molecular mechanisms regulating XIAP degradation and cleavage during chemotherapy-induced apoptosis in EOC cells;
and Aim 3. To identify markers for the rapid monitoring of response to chemotherapy. Understanding the molecular mechanism by which cancer cells become resistant to apoptosis will allow us to modulate the factor(s) controlling the apoptotic cascade and may provide a specific approach for new cancer therapies. In addition, the identification of sensitive and specific markers of chemo-response and the development of a rapid blood test that can be used for rapid point-of-care analysis of therapeutic response will not only enable individual tailoring of treatment but will also identify patients who are not responsive, hence sparing them the ill-effects of chemotherapy.
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