Novel Glutamine Antagonist JHU395 Suppresses MYC-Driven Medulloblastoma Growth and Induces Apoptosis

  • J Neuropathol Exp Neurol. 2021 Mar 22;80(4):336-344. doi: 10.1093/jnen/nlab018.
Khoa Pham  1 ,  Micah J Maxwell  2 ,  Heather Sweeney  2 ,  Jesse Alt  3 ,  Rana Rais  3  4 ,  Charles G Eberhart  1  5 ,  Barbara S Slusher  3  4 ,  Eric H Raabe  1  2  5
Affiliations
  • 1. From the Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
  • 2. Division of Pediatric Oncology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
  • 3. Johns Hopkins Drug Discovery, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
  • 4. Department of Neurology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
  • 5. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
PMID: 33712838 DOI: 10.1093/jnen/nlab018
Abstract

Medulloblastoma is the most common malignant pediatric brain tumor. Amplification of c-Myc is a hallmark of a subset of poor-prognosis medulloblastoma. MYC upregulates glutamine metabolism across many types of Cancer. We modified the naturally occurring glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) by adding 2 promoeities to increase its lipophilicity and brain penetration creating the prodrug isopropyl 6-diazo-5-oxo-2-(((phenyl (pivaloyloxy) methoxy) - carbonyl) amino) hexanoate, termed JHU395. This prodrug was shown to have a 10-fold improved CSF-to-plasma ratio and brain-to-plasma ratio relative to DON. We hypothesized that JHU395 would have superior cell penetration compared with DON and would effectively and more potently kill MYC-expressing medulloblastoma. JHU395 treatment caused decreased growth and increased Apoptosis in multiple human high-MYC medulloblastoma cell lines at lower concentrations than DON. Parenteral administration of JHU395 in Nu/Nu mice led to the accumulation of micromolar concentrations of DON in brain. Treatment of mice bearing orthotopic xenografts of human MYC-amplified medulloblastoma with JHU395 increased median survival from 26 to 45 days compared with vehicle control mice (p < 0.001 by log-rank test). These data provide preclinical justification for the ongoing development and testing of brain-targeted DON prodrugs for use in medulloblastoma.

Keywords
6-diazo-5-oxo-l-norleucine; Cancer metabolism; DON; Pediatric brain tumor; Prodrug.
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