To improve outcomes for women with advanced serous ovarian cancer it would be very helpful to have a therapeutic intervention that would increase the response to primary therapy, much as Herceptin does in women with Her2/neu positive breast cancer. Needed would be the novel therapeutic agent itself, and a means of identifying the women most likely to benefit from it. A way to identify the women least likely to achieve a complete response to standard therapy would be a first step in this direction. If successful, a product of the proposed work will be a molecular prognostic classifier validated for potential use in a Phase I trial. It will predict failure to respond to standard therapy by disease progression or persistence vs. a disease free interval of at least 20 months. In addition, as a result of the proposed work, therapeutic targets will have been identified for future development and testing in Phase I trials. Well over half of newly diagnosed women with ovarian cancer will die of their disease, and the relative resistance to standard chemotherapeutic agents displayed by most ovarian cancers represents a significant clinical challenge. To characterize the molecular abnormalities in ovarian cancer and to determine how these might relate to the differences in biological behavior displayed by these tumors, we have utilized cDNA microarrays to identify specific genes that are differentially expressed in normal vs. malignant ovarian tissue as well as in therapy responsive vs. therapy non-responsive ovarian cancers. We propose to extend these studies to validate and refine a molecular prognostic classifier that will identify those women with advanced (stage Ill/IV) ovarian cancer who are unlikely to respond to standard therapy. We will also functionally characterize genes that are differentially expressed in therapy responsive vs. therapy non-responsive ovarian cancer, emphasizing the potential role of these genes in mediating the response of ovarian cancer cells to standard chemotherapeutic agents. Our overall goals are to develop better prognostic markers that will aid in the optimal treatment of women with late stage serous ovarian cancer, and to identify novel therapeutic targets involved in the chemoresistance of ovarian cancer, the primary cause of treatment failure and death in women presenting with advanced disease.
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