Research And Grants

Targeting mitochondrial metabolism as a novel therapeutic strategy for treatment of Diffuse Midline Gliomas

Diffuse midline glioma (DMG) is a highly aggressive pediatric brain tumor with a dismal prognosis. A major treatment barrier is tumor hypoxia—low oxygen levels that reduce the effectiveness of radiotherapy and chemotherapy. Our recent research found that targeting mitochondrial metabolism, specifically by reducing oxygen consumption in tumor cells, can overcome hypoxia and improve treatment response. While the mitochondrial inhibitor phenformin showed promise, its clinical use is limited due to safety concerns, necessitating safer alternatives.

Through a high-throughput screen of FDA-approved drugs, we identified six candidates with mitochondrial inhibitory properties. Among them, berberine, sertindole, and penfluridol emerged as top candidates with strong anti-DMG effects. Berberine, used in traditional Chinese medicine, and the antipsychotic drugs sertindole and penfluridol all demonstrate excellent brain penetration and reduced tumor cell oxygen consumption in laboratory studies.

These drugs not only impair tumor metabolism but also slow tumor growth and enhance the effects of radiation. Our current work focuses on understanding their mechanisms of action, validating efficacy in preclinical models, and optimizing their use in combination with radiotherapy. This research aims to fast-track safer, more effective therapies for children with DMG and improve their currently grim outcomes.