# Targeting Nucleotide Metabolism to Overcome Therapy Resistance in Glioblastoma

> **NIH NIH R37** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $554,870

## Abstract

ABSTRACT
 Glioblastoma (GBM) is the most common aggressive primary brain tumor and is
uniformly fatal with a median survival of around 1.5 years. Like surgery and chemotherapy,
radiation (RT) is a critical treatment for nearly every patient with GBM and has repeatedly
improved patient survival in multiple randomized trials. Still, 80% of GBMs recur within the high
dose RT field. Thus, there is a critical need to develop strategies to overcome GBM RT-
resistance to further improve patient outcomes. GBM cells exhibit profound cancer-specific
metabolic abnormalities, including elevated purine synthesis, to fuel proliferation, invasion and
survival. We have found that the metabolic phenotype of elevated purine synthesis also
mediates resistance to RT in GBM by promoting the repair of RT-induced DNA damage. This
purine-mediated RT resistance can be overcome in preclinical models by mycophenolate mofetil
(MMF), an FDA-approved and CNS-penetrant inhibitor of purine synthesis. In this research
proposal we will determine how the RT response and purine synthesis regulate one another in
GBM. We will also determine if the GBMs with the greatest activity of purine synthesis derive
the greatest benefit from MMF treatment. Finally, we will perform a clinical trial to determine the
maximum tolerated dose of MMF given in combination with RT for patients with GBM and
confirm that this dose reaches active concentrations in GBM tissue. Together, these studies will
(1) Determine mechanistic links between the RT response and purine metabolism in GBM that
will facilitate the rational combination of metabolic inhibitors with DNA damage inducing
therapeutics, (2) Determine whether measuring purine synthesis rates could predict GBM
response to MMF treatment, and (3) Determine whether combined RT and MMF should be
evaluated in randomized trials for patients with GBM.

## Key facts

- **NIH application ID:** 10178518
- **Project number:** 1R37CA258346-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Daniel R Wahl
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $554,870
- **Award type:** 1
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10178518

## Citation

> US National Institutes of Health, RePORTER application 10178518, Targeting Nucleotide Metabolism to Overcome Therapy Resistance in Glioblastoma (1R37CA258346-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10178518. Licensed CC0.

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