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Myc-Driven Glycolysis Is a Therapeutic Target in Glioblastoma
Open accessPublished version of a preprint
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 13C 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.
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“For example, NAMPT inhibitors may be more effective in contexts of MYC-amplified glioblastoma (Tateishi et al., 2016) or when used in combination with other drugs known to deplete NAD+ pools (Bajrami et al., 2012; Chan et al., 2014).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Tateishi et al., 2016
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Metadata
- Authors
- Tateishi, K., Iafrate, A. J., Ho, Q., Curry, W. T., Batchelor, T. T., Flaherty, K. T., Onozato, M. L., Lelic, N., Sundaram, S., Cahill, D. P., Chi, A. S., & Wakimoto, H.
- Affiliations
- Harvard University (US)
- NYU Langone Health (US)
- Corresponding author
- Cahill, Daniel P.
- Chi, Andrew S.
- Wakimoto, Hiroaki
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2016-08-31
- Volume
- 22
- Issue
- 17
- Pages
- 4452-4465
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC5010492
- OpenAlex
- W2341529963
- Cited by
- 160
- References
- 50
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 11 · 2023: 21 · 2022: 22 · 2021: 28 · 2020: 21 · 2019: 15 · 2018: 3 · 2017: 10 · 2016: 3
- FWCI
- 4.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Japan Society for the Promotion of Science (16K10765)
- National Cancer Institute (K24CA125440, P50CA165962)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- glioblastoma, c-Myc, MYCN amplification, glycolysis, NAMPT inhibitors, cancer metabolism, metabolic targeting therapy, cancer stem cells, glucose flux, apoptosis, orthotopic xenograft
- MeSH terms
- Animals, Antineoplastic Agents, Disease Models, Animal, Gene Amplification, Glioblastoma, Glucose, Glycolysis, Humans, NAD, Proto-Oncogene Proteins c-myc, Apoptosis, Xenograft Model Antitumor Assays, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Mice, Nicotinamide Phosphoribosyltransferase
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