# Project 2: Overcoming GBM RT-resistance

> **NIH NIH P50** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $230,479

## Abstract

PROJECT SUMMARY/ABSTRACT (Project 2)
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. Recently, we have discovered that non-malignant cells in the
GBM microenvironment promote purine metabolism and RT resistance in glioma cells. In this
research proposal, we will (1) determine the metabolic mechanisms by which non-malignant cells
regulate GBM metabolism and RT resistance, (2) measure the activity of these metabolic
pathways in GBM tumors in patients and (3) interrupt this regulation in patients with GBM by
combining an FDA-approved and CNS-penetrant inhibitor of purine metabolism with standard of
care RT and temozolomide in a phase 1B clinical trial.

## Key facts

- **NIH application ID:** 10917028
- **Project number:** 5P50CA269022-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Daniel R Wahl
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $230,479
- **Award type:** 5
- **Project period:** 2023-08-14 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10917028

## Citation

> US National Institutes of Health, RePORTER application 10917028, Project 2: Overcoming GBM RT-resistance (5P50CA269022-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10917028. Licensed CC0.

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