Myc-Driven Glycolysis Is a Therapeutic Target in Glioblastoma.

Abstract

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, 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.

EXPERIMENTAL DESIGN:

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: Kensuke Tateishi, A John Iafrate, Quan Ho, William T Curry, Tracy T Batchelor, Keith T Flaherty, Maristela L Onozato, Nina Lelic, Sudhandra Sundaram, Daniel P Cahill, Andrew S Chi, Hiroaki Wakimoto
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 17 Pg. 4452-65 (Sep 01 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 27076630 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Proto-Oncogene Proteins c-myc
• RNA, Small Interfering
• NAD
• Nicotinamide Phosphoribosyltransferase
• Glucose

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (genetics)
• Cell Line, Tumor
• Disease Models, Animal
• Gene Amplification
• Glioblastoma (drug therapy, genetics, metabolism)
• Glucose (metabolism)
• Glycolysis (genetics)
• Humans
• Mice
• NAD (metabolism)
• Nicotinamide Phosphoribosyltransferase (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• RNA Interference
• RNA, Small Interfering (genetics)
• Xenograft Model Antitumor Assays