The overall goals of this project are to develop strategies to identify ovarian cancer patients least likely to respond to modern platinum/taxane-based treatments and to develop therapeutic strategies to attack cancer cells in these patients. This will be accomplished in two steps. First, we will develop and validate an accurate and clinically robust assay to identify patients that will survive less than 36 months after treatment with surgery plus platinum/taxane-based therapies. This approach builds on our discovery during the last project period that high-level amplifications of 8q24, 11q13, and 20q11-q13are strongly associated with reduced survival duration in patients treated with surgery plus platinum/taxane-based therapies. These data suggest that that an assay for amplification of these loci will identify a poorly performing subset of patients that can be offered alternative therapies. We will now develop and validate a clinically deployable assay for amplification at these loci. Both FISH and array CGH strategies will be evaluated. Second, we will develop siRNA and/or small molecule inhibitors for genes in regions of amplification at 8q24, 11q13, and/or 20q11- q13 that cause reduced apoptotic surveillance when over expressed. This work builds on our discovery of genes in regions of amplification at 8q24, 11q13, and 20q11-q13 that are over expressed when amplified. siRNA inhibitors of several of these genes decreased proliferation and/or increased apoptosis. siRNAs against PVT1 were particularly effective in inhibiting proliferation and in inducing apoptosis in cells in which PVT1 was amplified and over expressed. PVT1 inhibitors will be pursued at high priority initially. The most effective formulation will be developed for clinical application.
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