Abstract 2321: Comprehensive metabolic profiling of high MYC medulloblastoma revealed key differences between in vitro and in vivo in glucose and glutamine usage

Abstract

Abstract Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC is a hallmark of a subset of poor-prognosis medulloblastoma. In other cancers, high-level expression of MYC increase glutamine transport and fuels the TCA cycle, supporting cell growth and proliferation. However, the metabolism of high MYC amplified medulloblastoma subgroup remains underexplored. We performed comprehensive metabolic studies of xenografts of human MYC-amplified medulloblastoma tumors. We found that glucose was the main carbon source for TCA cycle. We also found that glutaminase ii pathway was the main pathway utilizing glutamine. In orthotopic xenografts, glutathione was the most abundant upregulated metabolite in tumor compared to normal brain. Glutamine derived glutathione was synthesized through glutamine transaminase K (GTK) enzyme in vivo, and it was significantly inhibited by glutamine analog 6-diazo-5-oxo-l-norleucine (DON). We engineered a DON prodrug with higher lipophilicity (JHU395) and found that JHU395 suppressed medulloblastoma growth in vitro and induced apoptosis. A single dose of JHU395 induced apoptosis in orthotopic D425 MED tumors but not in normal cerebellum or cortex. Twice weekly 15mg/kg dosing of JHU395 significantly extended the survival of the mice with D425 MED orthotopic xenografts (p<0.001 by log-rank test comparing treated vs vehicle control). Glutamine antagonists exploit MYC-amplified medulloblastoma's reliance on glutamine metabolism and may have therapeutic applications in human patients. Citation Format: Khoa Dang Pham, Bradley Poore, Allison Hanaford, Micah J. Maxwell, Heather Sweeney, Akhila Parthasarathy, Jesse Alt, Rana Rais, Barbara S. Slusher, Charles G. Eberhart, Eric H. Raabe. Comprehensive metabolic profiling of high MYC medulloblastoma revealed key differences between in vitro and in vivo in glucose and glutamine usage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2321.