CBIO-05. FATTY ACID OXIDATION IS REQUIRED FOR THE RESPIRATION AND PROLIFERATION OF MALIGNANT GLIOMA CELLS

Abstract

Glioma is the most common form of primary malignant brain tumour, with approximately 4 cases per 100,000 people per year. Gliomas, like many tumours, are thought to rely primarily upon aerobic glycolysis for energy production. However, high levels of glycolysis have been identified in brain tumours through the study of cells that have adapted to culture conditions (Michelakis et al. Sci Trans Med 2010); cells that have been cultured in the absence of serum have been shown to retain their original characteristics and are more suitable for chemical and genetic screening (Pollard et al. Cell Stem Cell 2008). Our findings demonstrate that primary-cultured human glioma cells grown under serum-free conditions require fatty acid oxidation to maintain respiratory and proliferative activity. Specifically, enzymes required for fatty acid oxidation are observed in cells within human glioblastoma tissue, fatty acid oxidation is the primary contributor to respiratory activity in cells isolated from human glioma, and this metabolic pathway is a limiting factor in the proliferation of human and mouse glioma cells cultured in the absence of serum. Moreover, pharmacological inhibition of fatty acid oxidation, using etomoxir, prolongs survival in a syngeneic mouse model of malignant glioma. Finally, we find that transcriptional upregulation of genes whose products play a role in fatty acid oxidation is significantly associated with lower survival in patients with low-grade glioma. Since fatty acid oxidation enzymes are present and functional in glioma tissues, this metabolic pathway could potentially be targeted to reduce energy production and cellular proliferation to provide therapeutic benefit to patients with malignant glioma. While there are currently several dozen under active clinical investigation for the treatment of glioma, there is a clear unmet need in this patient group and our data provide an entirely new pathway to target for the treatment of this cancer.