Therapeutic Micro RNA Strategies for Ovarian Cancer

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Epithelial ovarian cancer (EOC) is the most frequent cause of gynecologic malignancy-related mortality in women. Although advances in platinum/taxane-based chemotherapy have resulted in improved survival, patients typically experience disease relapse within 2 years of the initial treatment and develop resistance to therapy. Therefore, development of new therapies is a high priority. Molecular targeted drugs hold promise as independent therapeutic agents or chemotherapy response modifiers and could contribute substantial improvements to the outlook of women with EOC. microRNAs (miRNAs) are -22 nucleotide non-coding RNAs, which negatively regulate gene expression in a sequence-specific manner. We have generated the first evidence that miRNAs exhibit genomic alterations at high frequency and their expression is remarkably deregulated in ovarian cancer. This strongly suggests that miRNAs are involved in the initiation and progression of this disease. Indeed, our preliminary studies demonstrate that miRNA is a new class of novel biomarker with strong potential application to EOC in eariy detection, diagnosis and therapeutic response prediction. We hypothesize that miRNAs might serve two roles in the evolution of predictive and therapeutic strategies in EOC. First, it is possible that miRNAs might accurately predict response and resistance to a given chemotherapy. Second, and potentially more exciting in the long term, is the potential that selected mlRNA's might serve as therapeutic tools and/or chemotherapy response modifiers that will offer novel therapeutic opportunities for EOC. We propose the following specific aims to develop miRNA-based therapeutic tools for EOC. Specific Aim 1: Determine the function and therapeutic potential of select miRNAs in vitro. Specific Aim 2: Determine the therapeutic potential of select miRNAs in vivo. Specific Aim 3: Develop one or more constructs directed to specific mlRNA's in Phase l/ll trials. Specific Aim 4: Evaluate the predictive value of miRNAs response and resistance to a given chemotherapy. RELEVANCE (See Instructions): Epithelial ovarian cancer is the most frequent cause of gynecologic cancer-related mortality in women. miRNAs are small non-coding RNAs, which negatively regulate gene expression in a sequence-specific manner. We will conduct a detailed study of miRNA in ovarian cancer, which has not been carried out to date, with the intent to (i) discover new biomarkers for ovarian cancer clinical management or prognosis; (ii) discover novel and important therapeutic targets.