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 (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. METHODS The glycolytic dependency of Myc-driven GBM 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 GBM tumorspheres with and without MYC/MYCN amplification. The in vivo efficacy of glycolyic inhibition was tested using NAMPT inhibitors in MYCN 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 MYC/MYCN amplified patient-derived GBM tumorspheres. NAMPT inhibitors were potently cytotoxic, inducing apoptosis and significantly extended the survival of mice bearing MYCN amplified patient-derived GBM orthotopic xenografts. CONCLUSION 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 MYC or MYCN amplified GBM and potentially other cancers genetically driven by Myc.

Exploiting tumor vulnerabilities: NAD+-depleting agents combined with anti-tumor drugs as innovative strategy to treat hematological malignancies

“…Gene expression and protein analyses indicated that ibrutinib (also used to treat CLL and other lymphomas) unleashes strong upregulation of Nampt which makes these cells more susceptible to NAD + -depleting agents. Overall, as recently described for IDH1 mutant and MYC-overexpressing tumor cells [14,15], our study confirms metabolic pathway as TKI sensitizer. As a result, Nampt-targeting emerges as an effective approach not only when coupled to standard chemotherapy or radiotherapy, as previously reported, but also in patients receiving more modern, molecularly targeted agents, making them more effective (Figure 1).…”

Nicotinamide metabolism regulates glioblastoma stem cell maintenance

“…Targeting NNMT has proven beneficial for protection against diet-induced obesity through regulation of the SIRT1/NAMPT/NAD + pathway (64,74). Given the potential utility of NAMPT inhibitors in some gliomas, future studies may demonstrate the benefit of dual targeting of NNMT and NAMPT for glioma therapy (67,68).…”

An NAD + -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

“…NAMPT is expressed at high levels in several different cancers and, therefore, this enzyme has been considered a potential therapeutic cancer target (5,9,27). Recent studies in glioblastoma have indicated specific genetic subgroups may be exquisitely sensitive to NAMPT inhibition (28,29). IDH1 mutation sensitizes GSCs to NAMPT inhibitors due to low ambient levels of NAD + , resulting from downregulation of nicotinic acid phosphoribosyltransferase (NAPRT1), which catalyzes an alternative NAD + salvage pathway (29).…”

“…IDH1 mutation sensitizes GSCs to NAMPT inhibitors due to low ambient levels of NAD + , resulting from downregulation of nicotinic acid phosphoribosyltransferase (NAPRT1), which catalyzes an alternative NAD + salvage pathway (29). MYC overexpression and MYC or N-MYC amplification in glioblastoma cells increase glycolytic flux and lower NAD + levels, similarly leading to increased susceptibility to NAMPT inhibitors (28). The relevance of the NAMPT-E2F2-ID pathway to these specific molecular contexts is an interesting question for future investigation.…”