IGF::OT::IGF SBIR PHASE II TOPIC 290 RNAI SYNTHETIC LETHAL SCREEN IN CANCER CELL MODELS.

The DNA Damage and Repair (DDR) signaling modules are among the most commonly deregulated genes in human tumors. Deficiencies in DDR pathways are believed to influence tumorigenic processes by promoting a mutator phenotype, which contributes to the acquisition of genetic lesions and fuels malignant transformation. As DDR networks are extensively rewired in cancer cells, the concept of synthetic sickness/lethality (SL) can be exploited to identify novel therapeutic target(s) for cancer. RNA interference(RNAi) currently makes it possible to use high-throughput functional genomic strategies for SL target identification. Unfortunately, while RNAi has opened new avenues for improving the drug discovery process, these avenues remain only potential opportunities until we develop robust RNAi screening technologies, which include experimental and bioinformatics tools for drug target discovery, validation and integration into operational cell-based models. To address these issues, as outlined in the 290 SBIRcontract proposal, the development of a novel orthogonal functional genomics platform based on validated lentiviral shRNA libraries to facilitate the discovery of SL molecular targets en masse will be required. Accordingly, the ultimate goal of the 290SBIR research project is to develop and commercialize a human pooled SL shRNA library that targets all of the canonical and non-canonical DDR (400x400) gene combinations and to validate their application in RNAi screens in cancer cell models. This project will also require the development of supporting tools, including a public SL DDR database, protocols, reagents and software tools for in vitro screening, and the validation of the SL hits that specifically control the proliferation and survival of cancer cells. The aforementioned genetic screening and bioinformatic tools will provide the research community with highly modular and cost-effective approaches to understand and integrate dynamic changes in DDR signaling networks for the discovery of novelanti-cancer SL targets.