STMC-39. PRECISION FUNCTIONAL GENOMICS FOR GLIOBLASTOMA: IDENTIFYING MOLECULAR THERAPEUTIC TARGETS USING CRISPR-Cas9 AND RNAi TECHNOLOGIES DIRECTLY IN TUMOR 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, using 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 PKMYT1 and WEE1 activity. 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 tumors (e.g., PIK3CA activation vs. 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 weaknesses of applications of CRISPR-Cas9 technologies in patient samples. Collectively, our work illustrates the power of combining functional genetic te...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: STEM CELLS Source Type: research