Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma

Allison R Hanaford; Jesse Alt; Rana Rais; Sabrina Z Wang; Harpreet Kaur; Daniel L J Thorek; Charles G Eberhart; Barbara S Slusher; Allison M Martin; Eric H Raabe

doi:10.1016/j.tranon.2019.05.013

Orally bioavailable glutamine antagonist prodrug JHU-083 penetrates mouse brain and suppresses the growth of MYC-driven medulloblastoma

Transl Oncol. 2019 Oct;12(10):1314-1322. doi: 10.1016/j.tranon.2019.05.013. Epub 2019 Jul 21.

Authors

Affiliations

¹ Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, MD.
² Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine.
³ Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine; Department of Neurology, Johns Hopkins University School of Medicine.
⁴ Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO; Department of Biomedical Engineering, Washington University, St. Louis, MO.
⁵ Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21287; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, MD 21287.
⁶ Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, MD; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, MD 21287. Electronic address: allison.martin@einstein.yu.edu.
⁷ Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21287; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, MD 21287. Electronic address: eraabe2@jhmi.edu.

Abstract

A subset of poor-prognosis medulloblastoma has genomic amplification of MYC. MYC regulates glutamine metabolism in multiple cellular contexts. We modified the glutamine analog 6-diazo-5-oxo-l-norleucine (DON) to mask its carboxylate and amine functionalities, creating a prodrug termed JHU-083 with increased oral bioavailability. We hypothesized that this prodrug would kill MYC-expressing medulloblastoma. JHU-083 treatment caused decreased growth and increased apoptosis in human MYC-expressing medulloblastoma cell lines. We generated a mouse MYC-driven medulloblastoma model by transforming C57BL/6 mouse cerebellar stem and progenitor cells. When implanted into the brains of C57BL/6 mice, these cells formed large cell/anaplastic tumors that resembled aggressive medulloblastoma. A cell line derived from this model was sensitive to JHU-083 in vitro. Oral administration of JHU-038 led to the accumulation of micromolar concentrations of DON in the mouse brain. JHU-083 treatment significantly increased the survival of immune-competent animals bearing orthotopic tumors formed by the mouse cerebellar stem cell model as well as immune-deficient animals bearing orthotopic tumors formed by a human MYC-amplified medulloblastoma cell line. These data provide pre-clinical justification for the ongoing development and testing of orally bioavailable DON prodrugs for use in medulloblastoma patients.

Abstract

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