Title: the Metabolomic Signature of Malignant Glioma Reflects Accelerated Anabolic Metabolism Radiation Oncology

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT Although considerable progress has been made towards understanding glioblastoma biology through large-scale genetic and protein expression analyses, little is known about the underlying metabolic alterations promoting their aggressive phenotype. We performed global metabolomic profiling on patient-derived glioma specimens and identified specific metabolic programs differentiating low and high-grade tumors, with the metabolic signature of glioblastoma reflecting accelerated anabolic metabolism. When coupled with transcriptional profiles, we identified the metabolic phenotype of the mesenchymal subtype to consist of accumulation of the glycolytic intermediate phosphoenolpyruvate and decreased pyruvate kinase activity. Unbiased hierarchical clustering of metabolomic profiles identified three subclasses, which we term "energetic", "anabolic", and "phospholipid catabolism" with prognostic relevance. These studies represent the first global metabolomic profiling of glioma, offering a previously undescribed window into their metabolic heterogeneity, and provide the requisite framework for strategies designed to target metabolism in this rapidly fatal malignancy. Precis: Global metabolomic analysis identifies key features underlying the aggressive phenotype of malignant glioma, providing novel strategies for therapeutic intervention. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.