Myc-Driven Glycolysis Is a Therapeutic Target in Glioblastoma

摘要: Purpose: Deregulated Myc drives an oncogenic metabolic state, including pseudohypoxic glycolysis, adapted for the constitutive production of biomolecular precursors to feed rapid tumor cell growth. In glioblastoma, facilitates renewal tumor-initiating reservoir contributing maintenance. We investigated whether targeting Myc-driven state could be a selectively toxic therapeutic strategy glioblastoma. Experimental Design: The glycolytic dependency glioblastoma was tested using 13 C flux analysis, glucose-limiting culture assays, and glycolysis inhibitors, inhibitors NAD + salvage enzyme nicotinamide phosphoribosyl-transferase (NAMPT), in MYC MYCN shRNA knockdown lentivirus overexpression systems patient-derived tumorspheres with without / amplification. vivo efficacy glycolyic inhibition NAMPT -amplified orthotopic xenograft mouse models. Results: Enforced increased glucose expression enzymes cells. N-Myc demonstrated that activity determined sensitivity resistance glycolysis. Small-molecule particularly were –amplified tumorspheres. potently cytotoxic, inducing apoptosis significantly extended survival mice bearing xenografts. Conclusions: activation generates on addiction metabolites required Glycolytic via represents novel metabolically targeted or potentially other cancers genetically driven by Myc. Clin Cancer Res; 22(17); 4452–65. ©2016 AACR .