Description
Treatment of advanced ovarian cancer is eventually limited by acquired drug resistance to both taxanes and platinum. Multiple molecular mechanisms have recently been identified that are associated with paclitaxel resistance. In addition, the Fanconi Anemia pathway has been recently identified as being important in platinum resistance. This project looks to further explore the molecular mechanisms, which underpin intrinsic drug resistance and also look to identify mechanisms, which might be important in the acquired drug resistance phenotype.

Taxol and Carboplatin are drugs of major clinical importance in the treatment of women with ovarian carcinoma. However, a majority of patients will eventually suffer from relapse of their tumor and development of resistance to these and other chemotherapeutic 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 mechanisms 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/ BRCA pathway and their methylation as being potentially related to platinum resistance stemming from observations on the cisplatin hypersensitivity of cells from Fanconi-anemia patients. Genes identified through these cell-line studies now require validation in human tissue using different approaches. Intrinsic mechanisms of chemotherapy resistance have been recently studied by identifying transcriptional profiles of whole tumor specimens that correlate with recurrence at 21 months; but this study could be improved by using microdissected specimens and clearer clinical endpoints. 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:

1. 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 immuno-histochemistry in archived paired primary and recurrent tumor specimens.
2. Evaluate the role of Fanconi Anemia (FA)/BRCA gene family in initial cisplatin sensitivity and evolving platinum resistance by methylation studies of FA genes in matched sets of germ line, primary ovarian tumor, and recurrent tumor DNA.
3. 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.
   
   
   
   

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