At the time of presentation, most ovarian cancers are no longer dependent on single genetic determinants for growth and/or survival. Targeted therapies used as single agents will not work in this disease and thus second site lethality screens will help identify critical pathways to target in combination with novel biologics. Our objectives are to take genes obtained through our synthetic lethal siRNA screens, and use them to map the sensitization network for targeted therapeutics relevant to EOC, and design meaningful combinations of siRNAs with drugs, or drugs with drugs, that can be rapidly translated to the clinic. We have used RNAi approaches to identify candidates that selectively enhance killing by the Src-targeting agent, dasatinib (also known as BMS-354825, Sprycel""""""""). Mapping the pattern of hits back to the network map revealed suggestive clusters of closely interacting proteins, implying identification of key survival nodes. The three Aims proposed will systematically develop our preliminary studies to identify productive targets of co-inhibition, with the ultimate goal of identifying new drug combinations that will greatly enhance the treatment of women with EOC. Hence, Aims 1 &2 are designed to apply a series of in vitro filters to help prioritize selection of the optimal combination of proteins to target using clinically relevant therapies in animal models. Specifically, Aim 1 will refine our high-value list of validated dasatinib-sensitizing siRNAs by screening a set of EOC cell lines and primary cultures generated from ascites obtained from patient with ovarian cancer and cluster these sensitizing genes into coordinated groups based on network modeling, in vitro drug-drug synergy studies, and functional studies to be completed in this Aim.
In Aim 2, we will explore the expression patterns of proteins and transcripts for the refined hits identified in Aim 1 in patient samples to assess their pathological and clinical relevance.
In Aim 3, for the highest priority hits we will conduct drug pharmacokinetic and toxicity studies in animals using drug-drug combinations evaluated at various ratios as dictated by our in vitro synergy data. We will identify optimal dosage regimens and evaluate their therapeutic efficacy in xenograft animal models. For hits lacking clinically developed agents, we will perform siRNA-drug combinations in the animal models. We believe that this cutting-edge approach will yield a paradigm that can subsequently be applied for multiple therapeutic applications.
The studies proposed offer an unprecedented opportunity to employ a functional approach in designing combination therapies that can be applied to improve ovarian cancer treatment outcomes with contemporary agents such as dasatinib, with or without the front line chemotherapeutic agents, platinum and paclitaxel. They will also provide valuable preclinical resources regarding drug safety and dosage regimen to help design future clinical trials with combination therapy.
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