Comprehensive Characterization of the Apoptotic Machinery in Glioblastoma Identifies New Therapeutic Strategies

Effective treatments for cancer require the engagement of the apoptotic (cell death) machinery. These pathways have been implicated in the therapeutic efficacy of almost every chemotherapy, targeted agent, and even in some forms of immunotherapy. Inability to sufficiently engage the apoptotic machinery results in tumor survival and resistance. Glioblastoma (GBM), the deadliest form of brain cancer, has poor clinical response to almost every therapy, suggesting a heightened anti-apoptotic signature. In these studies, we are the first to comprehensively characterize the apoptotic machinery in patient-derived GBM samples through genetic, molecular, and functional measures. In the first portion of this work, we demonstrate how GBM are capable of utilizing multiple apoptotic blocks and how this versatility endows them with intrinsic resistance to standard of care. By understanding the intricacies in GBM apoptotic machinery, we are able to rationally design therapeutic strategies to exploit these dependencies, as highlighted by the second portion of this work