Bevacizumab treatment induces metabolic adaptation toward anaerobic metabolism in glioblastomas

• DOI: 10.1007/s00401-014-1352-5
• Publication Date: 2014-10-16T06:56:01Z
• Authors: Fred Fack; Heidi Espedal; Olivier Keunen; Anna Golebiewska; Nina Obad; Patrick N. Harter; Michel Mittelbronn; Oliver Bähr; Astrid Weyerbrock; Linda Stuhr; Hrvoje Miletic; Per Ø. Sakariassen; Daniel Stieber; Cecilie B. Rygh; Morten Lund-Johansen; Liang Zheng; Eyal Gottlieb; Simone P. Niclou; Rolf Bjerkvig
• Keywords: Anaerobic glycolysis; Lactate dehydrogenase A

Anti-angiogenic therapy in glioblastoma (GBM) has unfortunately not led to the anticipated improvement patient prognosis. We here describe how human GBM adapts bevacizumab treatment at metabolic level. By performing (13)C6-glucose flux analysis, we show for first time that tumors undergo re-programming toward anaerobic metabolism, thereby uncoupling glycolysis from oxidative phosphorylation. Following treatment, an increased influx of was observed into tumors, concomitant lactate levels and a reduction metabolites associated with tricarboxylic acid cycle. This confirmed by expression glycolytic enzymes including pyruvate dehydrogenase kinase treated tumors. Interestingly, L-glutamine were also reduced. These results further assessment vivo data obtained magnetic resonance spectroscopy positron emission tomography. Moreover, depletion glutathione indicating caused stress Confirming results, immunohistochemical analysis showed up-regulation bevacizumab-treated tumor core as well single cells infiltrating brain, which may explain invasion after treatment. observations validated panel eight patients paired biopsy samples before Importantly, adaptation is mediated clonal selection mechanisms, but represents adaptive response therapy.