MAPPING THE GLIOBLASTOMA METABOLOME AFTER BEVACIZUMAB THERAPY BY 13C6-GLUCOSE METABOLOMIC FLUX ANALYSIS.

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Abstract

BACKGROUND: Glioblastomas (GBMs) are highly vascular tumors. Therefore, anti-vascular therapy has been regarded as a promising treatment strategy. Yet, recent results from two double-blind, placebo-controlled phase III trials, (RTOG 0825), and (AVAglio), for first-line treatment of GBM patients did not show any improvement of overall survival. In order to provide new insight into how GBMs adapt to antivascular therapy we have performed a detailed 13C6-glucose metabolomic flux analysis of human GBM xenografts that show strong genotypic and phenotypic similarities to human GBMs in situ. This approach, together with functional MRI and PET imaging show that bevacizumab treatment leads to a significant reduction in intratumoral blood flow accompanied by an induction of hypoxia. METHODS: In order to delineate metabolomic changes iduced by bevacizumab therapy, we infused bevacizumab treated animals with 13C6-glucose 15 min and 120min. before the tumors were removed. We then performed a detailed LC-MS analysis of 13C-labelled metabolites as well as cold metabolites associated with glycolysis and the citric acid cycle (TCA-cycle associated with oxidative respiration). Analyses were performed on both tumors as well as normal adjacent brain tissue. RESULTS: We show that bevacizumab treatment induces an increased influx of glucose into the tumors, which is accompanied by an increase in metabolites associated with the pentose phosphate pathway (PPP). Also, levels of lactate dehydrogenase (LDHA) as well as lactate were increased in the treated tumors. Interestingly, bevacizumab treatment caused a reduction of metabolites associated with the TCA cycle. Moreover, the metabolomics analyses revealed reduced levels of glutamine in treated tumors indicating that alternative pathways fueling the TCA cycle are depleted. CONCLUSIONS: In sum, our results show that GBMs respond to bevacizumab therapy by up-regulating glycolysis, with a down-regulation of oxidative respiration. Importantly, the results indicate that through the PPP-shunt, enough energy is produced to drive tumor progression. How bevacizumab treatment should be combined with inhibitors of glycolysis will be discussed. SECONDARY CATEGORY: Tumor Biology.

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