TMET-24. Rewiring Metabolism to Reduce Hypoxia and Radioresistance in Diffuse Midline Gliomas: A Drug Repurposing Approach

Abstract Diffuse midline glioma (DMG) is a highly aggressive brain tumor that predominantly affects children. The prognosis for DMG remains dire, with survival rates remaining dismal despite ongoing research efforts. One major obstacle in treating brain tumors is hypoxia—a state of low oxygen within the tumor microenvironment. Hypoxia is a hallmark of many solid tumors and significantly impairs the effectiveness of therapies such as chemotherapy and radiotherapy, both of which depend on oxygen to generate reactive species that kill cancer cells. While efforts to increase tumor oxygenation have largely failed, our recent study found that targeting mitochondrial metabolism in DMG cells using the drug phenformin can reduce oxygen consumption and improve tumor sensitivity to radiotherapy. However, phenformin is no longer clinically available due to safety concerns, highlighting the need for safer and more effective alternatives. We conducted a large screen of FDA-approved drugs, and we identified several promising candidates with potential mitochondrial inhibitory effects. Among them, penfluridol emerged as promising candidate, showing both strong mitochondrial inhibition and potent anti-DMG activity. Penfluridol is an antipsychotic medication primarily used to treat schizophrenia, with excellent blood–brain barrier penetration. It acts as a dopamine receptor antagonist, mainly targeting the D2 receptor, and has demonstrated anti-cancer effects in various preclinical models. In vitro, penfluridol effectively reduces oxygen consumption in DMG cells and slows their proliferation. It also synergizes with radiotherapy, significantly reducing the surviving fraction of DMG cells. These findings suggest that penfluridol may mitigate hypoxia, inhibit tumor growth, and enhance radiotherapy efficacy. Our current focus is to further investigate the mechanism of action of penfluridol, assess its effectiveness in preclinical models of DMG, and explore strategies to optimize its therapeutic potential.