An exploration of the bioenergetics and therapeutic efficacy of a pharmacologically induced metabolic therapy in glioblastoma.

Abstract

Glioblastoma (GBM) is the most aggressive primary brain tumor. Pathogenesis is complex, with involvement of mitochondrial dysfunction, oncogenic signaling and metabolic rewiring. Targeting metabolic vulnerabilities of GBM remains challenging due to high intratumoral heterogeneity. We characterized the bioenergetic phenotypes of 3 distinct glioma stem cells (GSCs), as well as non-stem U87MG, testing the antiproliferative potential of metformin (MF), dichloroacetate (DCA), sodium oxamate (SOD) and diazo-5-oxo-L-norleucine (DON). We found that GBM27, highly oxygen-dependent, was the most resistant to all treatments except DON. DON decreased total ATP production, but demonstrated heterogeneous metabolic responses, suggesting a multidimensional role of glutamine in cellular bioenergetics. Effective targeting of oxygen-dependent GSCs would be toxic to normal cells. Circumventing toxicity entails dose-reduction strategies. Bleomycin exhibited therapeutically relevant synergistic effects with MF, DCA and DON in GBM27, and DON in all other cell lines. Archetypal of non-stem populations, U87MG was not able to adapt to long-term glucose and glutamine depletion despite the presence of ketone bodies. Cyclical ketone-compensated glucose depletion induced growth arrest, morphological changes, and a quiescent metabolic phenotype. Our study highlights the need for better characterization of GBM from a metabolic perspective. Exploiting cancer addiction to fermentable energy sources warrants further exploration