“To me, this community represents such a vibrant group of individuals who are united by the mission of ending brain cancer.”

About DSA-Funded Research

Heterogeneity at the level of genes, cells, and tissues is substantial in glioblastoma (GBM), undermining effective treatment for patients living with GBM. Preclinical animal models for target discovery are limited by low throughput, yet high throughput screens are often limited by lack of tumor heterogeneity. In recent Sontag Foundation funded work, we have developed high-throughput CRISPR-based platforms for discovering novel therapeutic targets and defining their mechanisms of action at single cell resolution in brain tumors. In vivo perturb-seq in GBM enables high-throughput, single cell genetic screens in intact glioma models and their tumor microenvironments, revealing DNA-PKcs as a leading target in GBM that sensitizes tumors to radiation therapy by acting through cancer cells and the immune microenvironment. The objective of this proposal is to define novel combination treatments for patients with GBM through investigation of DNA-PKcs and development of functional genomic tools that can quantify and predict the impact of the local immune and tissue environments on the functions of genetic targets. The central hypothesis is that DNA-PKcs and other genetic vulnerabilities revealed from our screens drive treatment resistance by shaping heterogeneous GBM tissue environments. Successful completion of this proposal establishes a novel functional genomic platform that can discover new GBM therapeutics within the context of tumor heterogeneity.