Scientists in the McBrayer Lab at CRI last year identified a metabolic pathway that can be targeted to stop an aggressive form of brain cancer known as Glioma.

These findings not only offer new insights into the biology of gliomas but also establish the basis of a clinical trial expected to begin next year.

Gliomas are among the most lethal and treatment-resistant human cancers. Standard treatment has not changed since 2005, and no new drugs have been approved for glioma therapy in the last decade. A significant portion of gliomas are initiated by mutations that affect IDH genes. These genes encode metabolic enzymes that, when mutated, cause profound metabolic changes in brain cells that cause them to become cancerous. While IDH inhibitors have been used to treat other cancers like leukemia, they are less effective against aggressive gliomas.

To find alternative treatment strategies, scientists in the McBrayer lab screened hundreds of drugs to identify those that preferentially kill glioma cells with IDH mutations. During this process, they discovered that IDH1 mutations increased the dependence of glioma cells on a specific metabolic pathway. Researchers then searched for drugs that could inhibit key enzymes in this pathway in the brain, given that classical inhibitors of this pathway do not readily cross the blood-brain barrier.

Researchers narrowed their search to one drug that targets a specific enzyme. Researchers found that it showed efficacy as a single agent in an array of IDH1 mutant glioma models, suggesting that it may have utility in treating brain tumors.

Coincidentally, a team led by Daphne Haas-Kogan, M.D., at the Dana-Farber Cancer Institute independently discovered that this drug also has activity against devastating pediatric brain tumors known as diffuse midline gliomas.

“These insights hold great promise for the development of precision medicine-based treatment strategies for patients with brain tumors,” said Samuel McBrayer, Ph.D., an Assistant Professor at CRI and one of the senior authors of the study. “We’re excited about the therapeutic potential of our findings and look forward to advancing our work to a clinical trial that is planned for next year.”