Repurposing Existing Drugs for Glioblastoma therapy: A Metabolic-Based Screening Strategy

Abstract

Glioblastoma (GBM), the most aggressive primary brain tumor in adults, presents a formidable clinical challenge with limited treatment options and a dismal prognosis. Our translational research project aims to discover existing drugs that can be repurposed to improve the effectiveness of temozolomide (TMZ) in treating GBM.

Our previous work, aimed at repurposing the first-generation antipsychotic chlorpromazine (CPZ), identified pyruvate kinase M2 (PKM2) as a key vulnerability in GBM cells, mediating the drug's antitumor efficacy by targeting this glycolytic enzyme. PKM2, a key regulator of the Warburg effect, drives GBM tumorigenesis by dynamically switching between its metabolically active tetrameric form and its oncogenic dimeric form. This study investigates a drug repurposing approach to identify clinically approved, brain-penetrant small molecules that can stabilize PKM2 in its tetrameric conformation, thereby disrupting the metabolic adaptability and oncogenic potential of GBM cells.

We implemented a multi-step screening strategy combining virtual screening, pharmacological data analysis, and robust in vitro cellular assays using both anchorage-dependent and -independent human GBM cell lines. From vast libraries of clinically approved drugs, three candidates emerged as promising hits. These compounds demonstrated significant inhibition of GBM cell viability, reduced nuclear localization of the dimeric, oncogenic PKM2 isoform, and impairment of the glycolytic activity. These findings strongly suggest their potential to attenuate the Warburg effect and curtail GBM malignancy, warranting their expeditious evaluation as adjunctive therapies in GBM clinical trials. Future research will delve into the precise mechanisms of action of these identified drugs, assess their potential for synergistic activity with TMZ (the current standard of care medication), and expand the search for novel PKM2-targeting molecules.