Targeting Lactic Acid Metabolism for Glioblastoma Therapy

Glioblastoma (GBM) is the most common primary malignant brain tumor with poor prognosis and essentially no durable treatment. Tumor growth is ultimately determined by nutrients/energy. Tumor tissues have developed unique strategies to enable their growth and to secure their survival under conditions of nutrient absence. Originally considered as a waste product of breaking down sugar for energy and probably better known from exercise physiology, lactic acid accumulates to a significant amount in the infiltrative edge of GBM tumors. We have made the intriguing observation that in clinically relevant model systems of glioblastoma, lactic acid is heavily utilized for energy in cell culture and more importantly in mouse models. Moreover, lactic acid is critical for glioblastoma cell survival when sugar levels are low. In order to mediate this survival benefit, lactic acid regulates the so called epigenome, which in part is comprised of chemical modifications on the DNA and proteins that ultimately regulate gene expression. Interference with lactic acid mediated regulation of the epigenome using a clinically validated drug, CPI-613 extends animal survival in mice. Following completion of the study our research will establish lactic acid metabolism as a therapeutic target in glioblastoma.