Abstract 390: Genome-wide CRISPR screens in brain tumor initiating cells (BTICs) identify potent sensitizers and resistors of conventional chemoradiotherapy
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AbstractGlioblastoma (GBM) is a highly aggressive and most common form of malignant primary brain tumors in adults (WHO grade IV). Despite surgical and therapeutic interventions, including chemotherapy with the alkylating agent Temozolomide (TMZ) and cranial irradiation, GBM relapse is inevitable with a median survival of <15 months. Extensive intratumoral heterogeneity in GBM is believed to be the leading cause of therapy resistance and disease relapse, suggesting that therapy acts as a bottleneck for tumor evolution. Recently, the advent of CRISPR-Cas9 technology has led to the development of genome-wide libraries of sgRNAs capable of introducing insertion-deletion (indels) within exonic regions of genes, leading to a frameshift mutation two-thirds of the time. Here, we present the first genome-wide CRISPR-Cas9 knockout screen in patient-derived GBM BTICs aimed to discover synthetic lethal sensitizers of conventional chemoradiotherapy. Briefly, we performed genome-wide CRISPR-Cas9 screens in treatment-naïve GBM BTICs subjected to in vitro chemotherapy with TMZ and irradiation. By comparing sgRNA dynamics at each doubling period, we were able to identify potent sensitizer genes exclusive to combined chemoradiotherapy, and not TMZ or irradiation alone. Candidate sensitizer genes were validated in an arrayed format to evaluate impact on GBM BTIC self renewal, proliferation, and sensitivity to TMZ and radiation. We aim to further validate these sensitizers of conventional chemoradiotherapy by performing a focused CRISPR-Cas9 genetic screen in our patient-derived xenograft model of treatment-refractory GBM. Ultimately, adjuvants targeting sensitizer genes could greatly enhance the impact of conventional chemoradiotherapy in GBM patients, leading to an increase in patient survival.Citation Format: Chirayu Chokshi, David Tieu, Kevin Brown, Chitra Venugopal, Parvez Vora, Katherine Chan, Amy Tong, Maleeha Qazi, Mohini Singh, Neil Savage, Andrea Habsid, Jason Moffat, Sheila Singh. Genome-wide CRISPR screens in brain tumor initiating cells (BTICs) identify potent sensitizers and resistors of conventional chemoradiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 390.
