PROJECT SUMMARY/ABSTRACT – Project 3 Despite decades of clinical trials, drug development, and technical advances in surgery and radiation oncology, glioblastoma (GBM) remains incurable. While radiotherapy is still one of the most effective treatment options for GBM, it cannot control the disease over time. This suggests that novel combination therapies are desperately needed to improve radiation treatment outcome for patients suffering from this disease. The studies outlined in this proposal are based on a hypothesis that is backed by our extensive preliminary data and published data. The overall hypothesis is that targeting radiation-induced phenotype conversion of non-stem GBM cells into radiation-resistant glioma-initiating cells using the dopamine receptor antagonist quetiapine (QTP) improves radiation responses, generates an exploitable metabolic vulnerability, and can be safely applied in patients with recurrent glioblastoma. The three aims of this study will address this hypothesis leveraging the unique resources and expertise available within the UCLA SPORE in Brain Cancer. Aim 1 will study effect sizes and the duration of changes in the mevalonate pathway in response to a novel combination therapy against GBM. Studies in Aim 2 will test the efficacy and safety of this combination therapy in patients with recurrent GBM. Finally, Aim 3 will study the effect of this combination therapy on glioma initiating cells and explore the underlying mechanisms.