Abstract 510: Novel glutamine antagonist JHU-395 suppresses MYC-driven medulloblastoma growth and induces apoptosis

Abstract

Abstract Medulloblastoma is the most common malignant pediatric brain tumor. Genomic amplification of MYC is a hallmark of a subset of poor-prognosis medulloblastoma. MYC upregulates glutamine metabolism, and medulloblastoma tumors with evidence of high glutamate have a poor prognosis. We modified the naturally occurring glutamine analog 6-diazo-5-oxo-l-norleucine (DON) to increase its lipophilicity and its stability in plasma, creating a prodrug termed JHU-395. We hypothesized that this prodrug would have enhanced cell penetration compared to DON and would kill MYC-expressing medulloblastoma. JHU-395 treatment caused decreased growth and increased apoptosis in human MYC-expressing medulloblastoma cell lines at lower concentrations than DON. In D283MED for example IC50 for DON is 20 uM while JHU 395 IC50 is 1 uM (p value < 0.05). Similar results were obtained with other high-MYC medulloblastoma cell lines, including D425MED and D341MED. JHU-395 induced apoptosis at low micromolar concentrations as measured by cleaved PARP Western blot and cleaved caspase 3 (CC3) immunofluorescence (60% CC3+ cells compared to 30% CC3+ in control p<0.05). Parenteral administration of JHU-395 in Nu/Nu mice led to the accumulation of micromolar concentrations of DON in brain as measured by mass spectrometry. These data suggest that JHU-395 may have activity against high MYC medulloblastoma in vivo, and testing this prodrug against MYC-driven medulloblastoma orthotopic xenografts is currently underway. Citation Format: Khoa Pham, Micah Maxwell, Heather Sweeney, Jesse Alt, Rana Rais, Barbara S. Slusher, Charles G. Eberhart, Eric H. Raabe. Novel glutamine antagonist JHU-395 suppresses MYC-driven medulloblastoma growth and induces apoptosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 510.