Abstract B14: Precision functional genomics for glioblastoma: Identifying molecular therapeutic targets using CRISPR-Cas9 and RNAi technologies in patient isolates

Glioblastoma (GBM) is the most aggressive and common form of adult brain cancer and is among the deadliest cancers, with a median survival of 15 months using standard-of-care therapies. Thus, improved treatments for GBM are desperately needed. To identify new GBM molecular therapeutic targets, our group has performed multiple functional genetic screens in patient-derived GBM stem-like cells (GSCs) and non-transformed human neural stem and progenitor cells (NPCs), which represent non-neoplastic controls. These screens, which have used both RNAi and CRISPR-Cas9 platforms, have led to the identification of several key molecular vulnerabilities in GSCs, including GBM-specific defects in: 3' splice site recognition, kinetochore function, and loss of redundancy between the kinase activities of PKMYT1 and WEE1. At this meeting we will present an overview of these studies, as well as our current efforts to: comprehensively retest all GBM-specific vulnerabilities scoring in these screens; address whether vulnerabilities arise from specific genetic alterations in patient samples (e.g. NF1 loss or PTEN loss); determine whether inhibition of specific molecular targets blocks tumor growth and/or maintenance; and demonstrate the mode of GBM-specific death for particular targets (e.g., cell cycle arrest, apoptosis, etc). In addition, we will highlight both strengths and limitations of applications of CRISPR-Cas9 technologies in patient samples. Collectively, our work illustrates the power o...
Source: Molecular Cancer Therapeutics - Category: Cancer & Oncology Authors: Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Poster Presentations - Proffered Abstracts Source Type: research