Grant: Project Grant

Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults. Current treatment for GBM (surgery, radiation and chemotherapy) extends survival but is ineffective at preventing disease recurrence due to the residual presence of tumor initiating "GBM stem cells" that evade therapy and patients will invariably succumb to the disease, on average, just 18 months after initial diagnosis. Genomics studies have identified a high degree of variability in the genetic make-up of GBM cells-both between patients and within the same patient-which has represented a major barrier to the efficacy of new therapies for this cancer. Recently, our group and others have identified two predominant subtypes of GBM stem cells that can both be isolated from patient tumor samples, indicating that curing a patient of all residual disease would require therapies that killed both subtypes. Herein, we propose to use cutting-edge CRISPR-Cas9 genome editing technology to determine which genes are required for the growth of each subtype, producing a roadmap of candidate therapeutic targets. By performing these genetic screens in a large panel of patient derived GBM stem cell lines generated by our collaborator, we will produce a powerful dataset highly reflective of the heterogeneity observed in the GBM patient population. Using this data, we will characterize the biological basis for subtype-specific gene dependencies, greatly increasing our understanding of the mechanisms of GBM progression. In addition, our screen data will allow us to nominate drugs and small molecules as potential new targeted therapeutic strategies which we will evaluate through both in vitro drug screening and in mouse models harboring human patient derived GBM tumors. In summary, our proposed study will strive to develop new therapeutic strategies that can be applied in combination to overcome tumor heterogeneity and successfully target both cell types and cure GBM.