Pharmacological and Chemical Approaches to Repurpose an Antiepileptic for Glioblastoma Treatment

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PROJECT SUMMARY / ABSTRACT Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with a dismal 5-year survival rate (~ 5 %). GBM metastasizes to different brain regions which makes surgical resection difficult. Despite radiation therapy and chemotherapy, the median survival timeline is dire at 15 months. The major challenges in GBM therapy include late diagnosis, metastasis, resistance to chemotherapeutics, and drug delivery issues due to blood-brain barrier. Thus, efforts towards developing novel pharmacotherapies for GBM are highly warranted. Cancer cells rewire their metabolic pathways that are intimately linked to oncogenes and tumor suppressor genes. The metabolic reprogramming confers GBM several advantages in survival, proliferation, metastasis, drug resistance, and immune evasion. In addition, recent research in the cancer metabolism field has revealed an important ‘lactate shuttle’ that explains the key role of lactate transfer from systemic circulation into tumor microenvironment. Lactate utilization is highly relevant for brain tumors such as GBM. Our long-term goal is to pharmacologically target tumor metabolic reprogramming for cancer therapy. Towards that goal, we screened a number of metabolic inhibitors in GBM cells that uncovered effectiveness of an FDA-approved antiepileptic drug stiripentol with its putative target lactate dehydrogenase. The objective of this study is to elucidate molecular mechanism and changes in cancer biology by stiripentol treatment in GBM cells and GBM in vivo models. In addition, we will study structure-activity relationships of novel derivatives identified from stiripentol scaffold to develop potent inhibitors. Additionally, formulations of stiripentol and potent lead compounds will be developed and tested in the tumor xenograft model of U87 xenografts. Our research will offer novel insights in the mechanistic pharmacology of stiripentol and can lead to the development of candidate therapeutics for GBM treatment.