Abstract 3549: C-MYC Sensitizes GBM with Primitive Features to Glutamine Metabolism Disruption

Abstract Glioblastoma (GBM) is among the most lethal of known human cancers, with a median survival of less than 15 months. The highly infiltrative nature and genetic heterogeneity of GBM renders treatment difficult. Therefore, better and more targeted therapies are needed for patients with GBM. There is a new WHO subset of GBM that contains primitive neuronal components (GBM-PNC). These tumors can arise from a histologically classic GBM, and often the GBM-PNC portions of the tumor contain C-MYC or N-MYC amplifications. High MYC expression is known to alter cellular metabolism, increasing reliance on glutamine, which may create opportunities for therapeutic intervention. We hypothesized that depriving GBM-PNC cells of glutamine using metabolic inhibitors would suppress growth and tumorigenicity. To create genetically appropriate GBM-PNC models, we derived cortex (CTX) human neural stem cells and transformed them through lentiviral expression of mutant p53, constitutively-active AKT and hTERT. Transformed neurospheres were then lentivirally transduced with either C-MYC or BMI1. These models formed aggressive tumors in mice and recapitulated the histological features of GBM with expression of NESTIN, GFAP, and MAP2. When treated with the glutamine metabolic inhibitors DON or Acivicin, transformed neurospheres that expressed C-MYC had decreased cellular proliferation (BrdU incorporation, P<0.05) and increased apoptosis (cleaved caspase-3 expression, P<0.05) while neurospheres expressing BMI1 had no statistically significant changes. Additionally, cells overexpressing C-MYC had an increased expression of glutaminase, an essential enzyme for glutamine incorporation into the TCA cycle. We hypothesize that C-MYC expression sensitizes GBM-PNET cancer cell lines to DON or Acivicin inhibition through greater reliance upon glutamine for its TCA cycle intermediates. In addition C-MYC upregulates multiple glutamine transporters, which may also be used to transport DON and/or Acivicin inside the cell, conferring increased sensitivity. After further validating glutamine metabolic inhibitors in orthotopic xenografts and investigating the mechanism of action by metabolomics, we anticipate that metabolic inhibitors may have a therapeutic role in GBM-PNC. Citation Format: Brad Andrew Poore, Isabella Taylor, Jeffrey Rubens, Allison Hanaford, Micah Maxwell, Charles Eberhart, Eric Raabe. C-MYC sensitizes GBM with primitive features to glutamine metabolism disruption [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3549. doi:10.1158/1538-7445.AM2017-3549