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

Translational Oncology (Oct 2019)

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

Affiliations

Allison R. Hanaford: Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
Jesse Alt: Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine
Rana Rais: Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine; Department of Neurology, Johns Hopkins University School of Medicine
Sabrina Z. Wang: Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
Harpreet Kaur: Division of Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
Daniel L.J. Thorek: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO; Department of Biomedical Engineering, Washington University, St. Louis, MO
Charles G. Eberhart: 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
Barbara S. Slusher: Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine; Department of Neurology, Johns Hopkins University School of Medicine
Allison M. Martin: 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; Address all correspondence to: Allison M. Martin, MD, Pediatric Hematology/Oncology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Van Etten 6A04B, Bronx, NY, 10461
Eric H. Raabe: 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; Address all correspondence to: Eric H. Raabe, MD, PhD, Bloomberg Children’s Center Rm 11379, Johns Hopkins Hospital, 1800 Orleans Street, Baltimore, MD 21287.

Journal volume & issue: Vol. 12, no. 10
pp. 1314 – 1322

Abstract

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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.

Published in Translational Oncology

ISSN: 1944-7124 (Print); 1936-5233 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/translational-oncology/

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