Abstract 5051: MYC-driven models of primitive neuroectodermal tumor are sensitive to inhibitors of glutamine metabolism.

Abstract

Abstract Brain tumors are a diverse group of cancers in which alterations in growth regulation pathways drive tumorigenicity. Histologically similar tumors may have significant differences in underlying molecular pathways and this in turn may have significant implications for the development of targeted treatment. The MYC family of proteins promotes proliferation and an aggressive phenotype in diverse cancers. Primitive Neuroectodermal Tumors (PNETs) are high grade tumors that can arise throughout the neuro-axis. One subset of PNETs is MYC amplified, and some PNETs are known to express LIN28A, a key regulator of MYC. MYC expression in tumors leads to increased reliance on glutamine metabolism (i.e. the Warburg effect). We hypothesized that MYC-driven PNET tumors would up regulate glutamine metabolism and that glutaminase inhibitors would selectively target MYC-driven tumors. We tested this hypothesis using the MYC-positive PNET cell line PFSK as well as MYC-transformed human neural stem cells. The glutamine methabolic inhibitors DON (6-Diazo-5-oxo-L-norleucine) and acivicin were used to disrupt glutamine metabolism in these cells. Using Tetrazolium dye reduction (MTT assay) and Bromodeoxyuridine assays (BrdU) as indicators for cell growth and replication, we found that PFSK growth is inhibited by acivicin at 10 micromolar concentration (MTT activity reduced by 88%, p<0.05, t-test acivicin treated compared to untreated) MYC-negative UW228 cells were resistant to DON and acivicin treatment. Similarly, DON or acivicin inhibited the proliferation of MYC-transformed human neural stem cells. We observed a 75% reduction in BrdU incorporation in MYC transformed cortex neural stem cells using acivicin, (p<0.001, t-test acivicin treated compared to vehicle treated), 60% reduction in cortex MYC cells using DON (p<0.05), and a 48% reduction in hindbrain MYC cells using DON (p<0.01). The growth of control MYC-negative cells was not significantly inhibited by either drug. This data shows that glutaminase inhibition limits cell replication in tissue culture models of MYC-driven PNET. We are currently investigating the mechanism of growth inhibition (e.g. apoptosis versus cell cycle arrest) caused by glutaminase inhibitors. Murine orthotopic xenograft experiments investigating the efficacy of DON and acivicin treatment in MYC-driven PNET are currently underway in our laboratory. Citation Format: Sama F. Ahsan, Allison Hanaford, Melanie Weingart, Isabella Taylor, Charles Eberhart, Eric Raabe. MYC-driven models of primitive neuroectodermal tumor are sensitive to inhibitors of glutamine metabolism. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5051. doi:10.1158/1538-7445.AM2013-5051