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

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.

• Authors: Khoa Pham, Micah J Maxwell, Heather Sweeney, Jesse Alt, Rana Rais, Charles G Eberhart, Barbara S Slusher, Eric H Raabe
• Journal: Journal of neuropathology and experimental neurology (J Neuropathol Exp Neurol) Vol. 80 Issue 4 Pg. 336-344 (03 22 2021) ISSN: 1554-6578 [Electronic] England
• PMID: 33712838 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 American Association of Neuropathologists, Inc. All rights reserved.

Chemical References

• Caproates
• Excitatory Amino Acid Antagonists
• JHU395
• Diazooxonorleucine
• Glutamine

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Caproates (chemistry, pharmacology, therapeutic use)
• Cell Line, Tumor
• Cerebellar Neoplasms (drug therapy, pathology)
• Diazooxonorleucine (analogs & derivatives, pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Excitatory Amino Acid Antagonists (chemistry, pharmacology, therapeutic use)
• Female
• Glutamine (antagonists & inhibitors, metabolism)
• Humans
• Medulloblastoma (drug therapy, pathology)
• Mice
• Mice, Nude