Investigating non-apoptotic cell death in glioblastoma

Summary Glioblastoma (GBM) is the most frequent and deadly primary brain tumor in adults; the median survival of patients with GBM remains a dismal 14-16 months. Resistance to apoptosis contributes to the dire outcome of patients with GBM. However, whether GBM tumors are susceptible to non-apoptotic forms of cell death remains largely unexplored. In new preliminary data, a library of molecularly and metabolically characterized patient- derived glioma models was interrogated for sensitivity to non-apoptotic cell death. This analysis demonstrates that GBM are extremely sensitive to inducers of a newly described form of non-canonical cell death that is dependent on the lipid palmitate and altered protein palmitoylation. This novel form of cell death is referred to as palmoptosis. Intriguingly, GBMs most susceptible to palmoptosis are enriched with specific molecular and metabolic characteristics consistent with a proneural subtype, suggesting a unique subset of GBM may be particularly vulnerable to tumor cell death mediated by palmoptosis. With a clinical drug available, these preliminary findings support the proposed aims which will define the mechanistic basis for GBM palmoptosis sensitivity and evaluate the therapeutic potential of targeting palmoptosis in clinically relevant GBM model systems. In Aim 1, the relationship between specific molecular and lipid metabolic features that render GBM susceptible to palmoptosis will be explored. Aim 2 investigates the role of protein palmitoylation in triggering GBM sensitivity to palmoptosis. Finally, Aim 3 will evaluate whether apoptosis-resistant models of GBM, which include in vivo models of recurrent GBM, are vulnerable to palmoptosis. Together, the proposed studies will provide the first investigation into whether a novel, non-canonical form of cell death can be exploited in GBM.