Glioblastoma (GBM) is the most frequent and highly malignant form of brain cancer. New therapeutic regimens are urgently needed as GBM patients present with a minimal response to currently-approved therapies. The goal of this project is to identify new therapeutic vulnerabilities and strategies for GBM using mouse models that recapitulate the formation and development of gliomas in vivo. To elicit therapeutic efficacy, our strategy is to co-target distinct hallmarks that tumors acquire for growth and progression. Encouraged by the unpublished report from our lab where a significant enhancement in therapeutic efficacy was observed upon combination of autophagy-activating agents with a VEGF inhibitor, we are planning to further refine this discovery and screen for other possible combinations that would improve the survival. The pre-clinical trials will involve treatments with agents that are either already approved or under clinical investigation as single agents: 1. Autophagy-associated agents: imipramine (tricyclic antidepressant) w/wo clopidogrel (P2Y12 inhibitor) 2. Alternatives to bevacizumab: small molecule inhibitors of VEGF/VEGFR signaling 3. Mechanism-targeted drugs, including c-Met, PI3K/mTOR and CDK1/2/4/6 inhibitors 4. Immunomodulatory agents, including immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, anti-CTLA4) We will then try to elucidate the mechanisms behind the potential efficacy for the most promising combinations by utilizing mouse models of GBM, complemented by assays with 2D in vitro culture or 3D GBM organoids. In addition, we will determine if gliomas develop resistance to chosen regimens and try to deconvolute the mechanisms of relapse. We will employ omics strategies to analyze tumors at the time when they respond and relapse to apply novel therapeutic interventions that could provide long-term management of the disease. The best strategies will be then evaluated in GBM patients in Phase 0 trials at the Ivy Brain Tumor Center.