Defining double-stranded RNA receptor induced apoptosis in ovarian cancer.

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DESCRIPTION (provided by applicant): Ovarian cancer accounts for 6% of cancer deaths in women. This heterogeneous disease circumvents our best treatments forcing us to develop novel drug targets that will induce ovarian cancer cell death. Innate immune receptors, like the dsRNA receptors melanoma differentiation-associated gene 5, dsRNA- dependent protein kinase receptor, retinoic acid inducible gene I and Toll-like receptor 3, are expressed on tumor cells and can act as powerful switches to initiate an apoptotic signal. Our preliminary data has identified ovarian cancer cell lines that die upon dsRNA simulation (responsive) or survive (non-responsive) that can serve as model systems to develop permissive versus restrictive biomarkers for dsRNA-based therapy development. All our cell lines (CAOV-3, OVCAR-3, D0V13 and SKOV-3) express mRNA for the dsRNA receptors but only CAOV-3 and 0VCAR3 upregulate dsRNA receptor expression when stimulated and subsequently undergo apoptosis. This model system offers us the opportunity to define the mechanistic details of the dsRNA-induced apoptotic response and investigate survival pathways in our non-responsive cell lines that could be targeted for dsRNA/survival pathway antagonist dual therapies. PUBLIC HEALTH RELEVANCE: Ovarian cancer is the most lethal of all gynecological cancers. Novel chemotherapeutics coupled to biomarkers that will identify responsive patients would allow physicians to determine the most efficacious method of treatment for each patient. This project seeks to define biomarkers that would identify dsRNA-responsive ovarian cancer tumors.