Taxol and Carboplatin are drugs of major clinical importance in the treatment of ovarian carcinoma; but the majority of patients will eventually develop resistance to these drugs. Molecular mechanisms in the development of drug resistance might involve genetic properties of tumors acquired during chemotherapy as well as intrinsic genetic properties of the tumors that contribute to resistance. The types of studies that may be useful for defining mechanism of drug resistance include in-vitro studies on cell lines and transcriptional profiling studies in human specimens. We have developed extensive preliminary in-vitro data on transcripts linked to Taxol resistance. Other cell line data have identified genes in the Fanconi Anemia (FA)/BRCA pathway and their methylation as being potentially related to platinum resistance stemming from observations of the cisplatin hypersensitivity of cells from Fanconi-anemia patients. This project seeks to build upon preliminary work by the investigators addressing acquired mechanisms of drug resistance as well as exploring robust transcriptional models addressing intrinsic mechanisms of drug resistance by the following specific aims. First, evaluate the expression of a refined list of about 50 transcripts linked to Taxol resistance in cell lines using either quantitative PCR comparing primary and recurrent paired tumors or immunohistochemistry in archived paired primary and recurrent tumor specimens. Second, evaluate the role of FA/BRCA gene family in initial platinum sensitivity and evolving platinum resistance by methylation and functional studies of FA genes and pathway in matched sets of germ line, primary ovarian tumor, and recurrent tumor DNA. Third, evaluate gene expression profiles in micro-dissected epithelial cells from primary ovarian cancer tumor specimens that distinguish women who had clinical remission for at least one year versus those who relapsed within six months of completing therapy. This project is designed to identify genes and/or pathways that are associated with intrinsic or acquired mechanisms of Taxol and Carboplatin resistance with the ultimate goal of identifying potential therapeutic targets for future drug development.
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