# Novel brain penetrant metabolic inhibitors to treat MYC-driven medulloblastoma

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $384,346

## Abstract

PROJECT SUMMARY
Medulloblastoma is the most common malignant brain tumor in children. Current treatment includes radiation
and multiple chemotherapies which cause severe acute and significant long term side effects. Despite this
aggressive treatment, a subset of patients called “Group 3 MYC-amplified medulloblastoma” have a survival rate
less than 25%. We and others have shown that MYC-amplified cancers change their energy metabolic
requirements and become “glutamine addicted” for their growth and survival. We have developed syngeneic
human neural stem cell models which are +/- MYC. Recently we found that the MYC-amplified cells are
exquisitely sensitive to the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON), while equally aggressive
cells without MYC expression as well normal human neural stem cells are unaffected. While promising, DON is
not clinically available. Its development was halted due to gastrointestinal (GI) toxicities, as the GI system is
highly dependent on glutamine utilization. Moreover, DON's brain penetration is limited. To overcome DON's
peripheral toxicities and to enhance its delivery to brain tumors, we created unique DON prodrugs. They were
designed to circulate intact as inert prodrugs in plasma, but permeate and be cleaved to release DON once
inside the brain. Compared to equimolar doses of DON, when our lead prodrug JHU-333 was evaluated in vivo
(mice, swine, and primates) it resulted in significantly less DON exposure in plasma, and was preferentially
biotransformed to DON in the brain, providing a 7-10-fold improvement in the brain/plasma ratio with substantially
less GI toxicity. When tested in our MYC-amplified Group 3 orthotopic xenograft model, our brain-penetrable
DON prodrug significantly increased survival following oral administration without overt toxicity. Although
promising, JHU-333 is not ideal for translational as it exhibits high clearance with a short t1/2 (0.5-2hr). Thus, our
main drug discovery focus will be to create metabolically stable DON prodrugs that permeate and are retained
in the brain so that their target inhibition can be sustained. In this grant, two PIs with complimentary expertise
will design novel DON prodrugs with optimized pharmacokinetic parameters and characterize their
efficacy/toxicity profiles in Group 3 MYC-amplified medulloblastoma mouse models. At the completion of these
studies we will have developed novel, robust, brian penetrant, and safe inhibitors of glutamine metabolism, laying
the ground-work for their rapid introduction into clinical trials.

## Key facts

- **NIH application ID:** 10007913
- **Project number:** 5R01NS103927-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Eric Hutton Raabe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $384,346
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10007913

## Citation

> US National Institutes of Health, RePORTER application 10007913, Novel brain penetrant metabolic inhibitors to treat MYC-driven medulloblastoma (5R01NS103927-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10007913. Licensed CC0.

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