Medicine, Human Health Technology Offers Page 29

RAMOT at Tel Aviv University Ltd. posted this:

Synthetic lethality occurs when a perturbation of two nonessential genes is lethal. This phenomenon offers a unique opportunity to develop selective anticancer drugs that will target a gene whose Synthetic Lethal (SL)-partner is inactive only in the cancer cells. Towards the realization of this potential, screening technologies have been developed to detect SL-interactions in model organisms and in human cell lines. However, currently their scope falls short compared to the large spectrum of interactions that need to be surveyed in cancer. Here we present a data-driven computational pipeline for the genome-wide identification of SL-interactions in cancer, by analyzing large volumes of genomic profiles of cancer cell lines and clinical samples. Our approach is first shown to successfully capture the SL-partners of tumor suppressors and oncogenes, according to six published experimental SL-screens. Second, we construct the first genome-wide network of SL-interactions in cancer and demonstrate its utility in predicting gene essentiality in a cancer-specific manner. Third, we show that, as predicted, underexpression of SL-partners has a strong positive prognostic value for cancer survival. Fourth, we identify synthetic lethality arising from gene over-activation and show that it can be utilized to predict anticancer drug efficacy. Lastly, we develop a complementary computational approach that by harnessing the obtained SL-networks identifies the most suitable treatment per patient, and identifies novel anticancer drug-targets, providing drug repurposing leads. Our approach provides a solid basis guiding future experimental studies aimed at developing new, selective anticancer therapies. Project ID : 2-2013-713
A novel approach for a genome-wide detection of synthetically-lethal genes in cancer: Towards rational drug target identification and personalized treatments