We are using distinct strategies to identify and validate novel synthetic lethality targets, including a synthetic lethality target discovery platform. This platform includes synthetic lethality screening libraries, bioinformatics and functional validation.
Our discovery platform for identifying novel synthetic lethality targets and associated biomarkers includes a differentiated functional screen based on Dual CRISPR. Using this technique, synthetic lethality targets are identified through simultaneous knockout of two genes in selected human cell lines. In an initial screen, one of the genes being perturbed is a known tumor suppressor gene and thus, a clinically-active biomarker, and the other gene encodes a putative synthetic lethality target which we believe is druggable using small molecules. We have been developing our synthetic lethality target discovery library in collaboration with Trey Ideker, Ph.D. at UCSD. In our initial Dual CRISPR Library 1.0, we are evaluating a set of approximately 50,000 independent gene knockout combinations.
We also identify and/or validate new biomarker-enabled targets using bioinformatics, including data analytics, biostatistics, and computational biology. As part of this approach, we interrogate public and proprietary databases comprising human tumor genetic information and specific cancer-target dependency networks. Such databases include Novartis’ Project Drive, which contains data points generated from approximately 7,800 genes, representing approximately one-third of the human genome, selectively knocked out using a single CRISPR gene editing approach across approximately 400 patient-derived cancer cell lines. Other databases we reference include The Cancer Genome Atlas, or TCGA, the Broad Institute’s Project Achilles, Memorial Sloan Kettering Cancer Center’s IMPACT, American Association for Cancer Research’s Project GENIE, Foundation Medicines’ FoundationInsights, Cancer Cell Line Encyclopedia, Genomics England’s 100,000 Genomes Project, and National Institutes of Health’s Genotype-Tissue Expression Portal. Collectively, such bioinformatics efforts supplement data from our synthetic lethality Dual CRISPR libraries to provide a comprehensive approach to identify and validate novel targets for which we discover and develop small molecule product candidates.