Project 2: Functional Genetic Networks for Systems-Guided Precision Medicine

CCMI v2.0 Project 2: Functional Genetic Networks for Systems-Guided Precision Medicine Project Leads: Prashant Mali and Stephanie Fraley; Co-Investigators: Alan Ashworth, Jennifer Grandis, Silvio Gutkind, Trey Ideker, and Laura van ’t Veer. SUMMARY Precision medicine aims to tailor therapies to the genetic and molecular background of a patient’s tumor. The development of such therapies faces numerous obstacles, many deriving from our ignorance of the genetic networks underlying tumorigenesis and the mechanisms of possible interventions. To clarify the genetic logic that governs therapeutic efficacy, Project 2 will use CRISPR/Cas9 genetic perturbation methodologies in an ensemble of combinatorial, functional, and mechanistic screens. Screens will focus on the PI3K pathway, the p53 tumor suppressor, and the protein systems mutated in invasive breast cancer (BRCA), head and neck squamous cell carcinoma (HNSCC), and lung squamous cell carcinoma (LUSC), pathways and diseases that together result in well over one million deaths each year worldwide. This focus will enable us to interrogate a broad collection of cell lines, experiments, and microenvironmental conditions. First, we will build on significant preliminary data to establish maps of synthetic lethal and epistatic genetic interactions centered on frequently mutated genes and therapeutic targets in the above pathways and cancer subtypes (Aim 1). Second, we will couple CRISPR/Cas9 screening to a panel of scalable functional assays for large-scale measurement of cancer phenotypes beyond cell proliferation (Aim 2). Third, we will pilot a new technology, STAG-CRISPR, to link CRISPR/Cas9 screening to real time molecular events in living cells, providing access to an even deeper array of phenotypes that have been recalcitrant to systems genetics thus far (Aim 3). Finally, to facilitate clinical translation of the identified gene-gene, gene-phenotype, gene-mechanism and gene-drug interactions, we will apply our extensive library of BRCA, HNSCC, and LUSC patient-derived xenograft (PDX) models to test compelling leads in vivo. We will also validate the identified interaction networks with patient data from the BRCA I-SPY 2 trial and from HNSCC patients at UCSD (Aim 4). Taken together, our integrated approach establishes a network of extensively validated interactions among genes, drugs and multiple phenotypic endpoints to advance the practice of precision oncology.