Abstract 504: Glutamine metabolic inhibitors suppress growth and tumorigenicity in MYC and MYCN-driven pediatric malignancies

Abstract

Abstract The MYC family of oncogenes is associated with aggressive pediatric cancers such as medulloblastoma and neuroblastoma. These transcription factors promote oncogenesis in part by altering cellular metabolism. In multiple types of cancer, high-level MYC expression drives increased glutamine metabolism. We hypothesized that MYC-driven medulloblastoma and MYCN amplified neuroblastoma would be sensitive to the glutamine metabolic inhibitors 6-diazo-5-oxo-l-norleucine (DON) and Acivicin. These drugs have previously be used in pediatric clinical trials, but never extensively clinically tested in MYC-driven malignancies. The high MYC medulloblastoma cell lines D425Med and D283Med experienced an 82% decrease in growth as measured by MTS assay when treated with Acivicin or DON (p<0.004). DON and Acivicin treatment also caused a 400% increase in apoptosis as measured by cleaved caspase-3 immunofluorescence (p<0.03). In human neural stem cells transformed with MYC, Acivicin treatment decreased proliferation by 50% as measured by BrdU incorporation (p<0.003) and increased apoptosis by over 100% as measured by cleaved caspase-3 immunofluoresence (p<0.0001). Human neural stem cells immortalized with SV40 were unaffected by Acivicin and DON treatment (p = 0.1). In mice with D283Med flank xenografts, Acivicin decreased the size of tumors by 70%. DON treatment decreased the volume of flank tumors by 94% in animals with D425Med xenografts (p = 0.001). In mice with D425Med cerebellar xenografts (p = 0.0018), DON tripled median survival from 26 to 90 days in animals with. The MYCN amplified neuroblastoma cell lines LAN5 and IMR32 were also sensitive to treatment with DON and Acivicin. DON and acivicin treatment significantly decreased proliferation as measured by BrdU incorporation (p<0.03) and significantly increased apoptosis as measured by cleaved caspase-3 immunofluroescence (p<0.003). The non-MYCN amplified neuroblastoma cell line SKNAS was resistant to treatment with both DON and Acivicin, suggesting that expression confers sensitivity to glutamine analogs. These data suggest glutamine metabolism is a therapeutic target in medulloblastoma and neuroblastoma with elevated MYC or MYCN levels, and potentially other pediatric cancer types associated with MYC oncogenes. Citation Format: Allison Hanaford, Catherine Guerra, Charles Eberhart, Eric Raabe, Antoinette Price. Glutamine metabolic inhibitors suppress growth and tumorigenicity in MYC and MYCN-driven pediatric malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 504. doi:10.1158/1538-7445.AM2015-504