title: Myc-Driven Glycolysis Is a Therapeutic Target in Glioblastoma.
abstract: OBJECTIVE
  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, 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 glioblastoma.
  
  
  METHODS
  The glycolytic dependency of Myc-driven glioblastoma was tested using (13)C metabolic flux analysis, glucose-limiting culture assays, and glycolysis inhibitors, including inhibitors of the NAD(+) salvage enzyme nicotinamide phosphoribosyl-transferase (NAMPT), in MYC and MYCN shRNA knockdown and lentivirus overexpression systems and in patient-derived glioblastoma tumorspheres with and without MYC/MYCN amplification. The in vivo efficacy of glycolyic inhibition was tested using NAMPT inhibitors in MYCN-amplified patient-derived glioblastoma orthotopic xenograft mouse models.
  
  
  RESULTS
  Enforced Myc overexpression increased glucose flux and expression of glycolytic enzymes in glioblastoma 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 MYC/MYCN-amplified patient-derived glioblastoma tumorspheres. NAMPT inhibitors were potently cytotoxic, inducing apoptosis and significantly extended the survival of mice bearing MYCN-amplified patient-derived glioblastoma orthotopic xenografts.
  
  
  CONCLUSIONS
  Myc activation in glioblastoma 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 MYC or MYCN-amplified glioblastoma and potentially other cancers genetically driven by Myc. Clin Cancer Res; 22(17); 4452-65. ©2016 AACR.
authors.affiliation: Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Tateishi
authors.affiliation: Department of Pathology, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.affiliation: Department of Pathology, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Quan
authors.initials: Q
authors.lastname: Ho
authors.affiliation: Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: William T
authors.initials: WT
authors.lastname: Curry
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. Stephen E. and Catherine Pappas Center for Neuro-Oncology, Department of Neurology, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Department of Pathology, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Maristela L
authors.initials: ML
authors.lastname: Onozato
authors.affiliation: Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nina
authors.initials: N
authors.lastname: Lelic
authors.affiliation: Stephen E. and Catherine Pappas Center for Neuro-Oncology, Department of Neurology, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sudhandra
authors.initials: S
authors.lastname: Sundaram
authors.affiliation: Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. chia01@nyumc.org hwakimoto@mgh.harvard.edu cahill@mgh.harvard.edu.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Cahill
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York. chia01@nyumc.org hwakimoto@mgh.harvard.edu cahill@mgh.harvard.edu.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Chi
authors.affiliation: Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. chia01@nyumc.org hwakimoto@mgh.harvard.edu cahill@mgh.harvard.edu.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Wakimoto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005784:Gene Amplification; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D051379:Mice; D009243:NAD / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; D005947:Glucose