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 (GBM), Myc facilitates renewal of the tumor initiating cell reservoir contributing to tumor maintenance. We investigated whether targeting the Myc-driven metabolic state could be a selectively toxic therapeutic strategy for GBM. Experimental Design: The glycolytic dependency of Myc-driven GBM was tested using <sup>13</sup>C metabolic flux analysis, glucose-limiting culture assays and glycolysis inhibitors, including inhibitors of the NAD+ salvage enzyme nicotinamide phosphoribosyl-transferase (NAMPT), in <i>MYC</i> and <i>MYCN</i> shRNA knockdown and lentivirus overexpression systems and in patient-derived GBM tumorspheres with and without <i>MYC</i> and <i>MYCN</i> amplification. The in vivo efficacy of glycolyic inhibition was tested using NAMPT inhibitors in <i>MYCN</i> amplified patient-derived GBM orthotopic xenograft mouse models. Results: Enforced Myc overexpression increased glucose flux and expression of glycolytic enzymes in GBM cells. Myc and N-Myc knockdown and Myc overexpression systems demonstrated that Myc activity determined sensitivity and resistance to inhibition of glycolysis. Small molecule inhibitors of glycolysis, particularly NAMPT inhibitors, were selectively toxic to <i>MYC</i>/<i>MYCN</i> amplified patient-derived GBM tumorspheres. NAMPT inhibitors were potently cytotoxic, inducing apoptosis and significantly extended the survival of mice bearing <i>MYCN</i> amplified patient-derived GBM orthotopic xenografts. Conclusions: Myc activation in GBM generates a dependency on glycolysis and an addiction to metabolites required for glycolysis. Glycolytic inhibition via NAMPT inhibition represents a novel metabolically-targeted therapeutic strategy for <i>MYC</i> or <i>MYCN</i> amplified GBM and potentially other cancers genetically driven by Myc.
- Received September 16, 2015.
- Revision received March 8, 2016.
- Accepted April 8, 2016.
- Copyright ©2016, American Association for Cancer Research.