# De Novo Nucleotide Synthesis as a Mediator of Radiation Resistance and a Therapeutic Target in Glioblastoma

> **NIH NIH K08** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $255,400

## Abstract

This K08 proposal will complete Dr. Daniel R. Wahl, MD, PhD’s training towards his long-term
career goal of directing an independent research program that aims to improve treatments for patients
with glioblastoma (GBM) by understanding interactions between abnormal GBM metabolism and the
radiation response. Dr. Wahl is an Assistant Professor of Radiation Oncology in the Department of
Radiation Oncology at the University of Michigan with established success in the field of radiation
oncology. This proposal builds on Dr. Wahl’s previously acquired expertise in radiation biology and the
mechanisms of metabolically-targeted drugs to develop expertise in flux-based metabolomics studies,
bioinformatics analyses of large data sets and advanced mouse modeling of GBM. These established and
newly-acquired skills will be integrated to improve our understanding of how metabolic adaptation
interactions with the radiation response and to test new therapeutic options for patients with GBM. The
work proposed herein will be conducted under the guidance of primary mentor Theodore S. Lawrence,
MD, PhD and co-mentors Maria Castro PhD and Charles A. Burant MD, PhD and an advisory team of
accomplished investigators with expertise in the fields of metabolomics, mouse modeling of GBM and
computational biology as well as a long track record of mentroring success. This 5-year plan includes
formal coursework, professional development and progressively independent research, with defined
milestones to ensure productivity and a successful transition to independence.
 Nearly all glioblastoma (GBM) recur within the high dose radiation field. We previously showed
that inhibiting abnormal metabolism in GBM is an effective strategy to abrogate radiation-resistance. We
have since performed an unbiased metabolomic analysis of 23 genetically distinct GBM cell lines, which
has implicated de novo purine and pyrimidine synthesis as the metabolic pathways most associated with
radiation resistance in GBM. For the work proposed in this K08 Award, we will use flux-based
metabolomics, patient-derived xenograft models of GBM and FDA-approved inhibitors of de novo
nucleotide synthesis to test the hypothesis that ionizing radiation directly increases the activity of de novo
purine and pyrimidine synthesis in GBM and that inhibition of these pathways will augment radiotherapy
by blunting the DNA damage response. Because the terminally-differentiated cells that comprise normal
brain predominantly rely on nucleotide salvage rather than de novo synthesis and because already FDA
approved drugs targeting these pathways are well-tolerated in patients, we believe that de novo
nucleotide synthesis may be a promising therapeutic target for selective radiosensitization in GBM.

## Key facts

- **NIH application ID:** 9976480
- **Project number:** 5K08CA234416-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Daniel R Wahl
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $255,400
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976480

## Citation

> US National Institutes of Health, RePORTER application 9976480, De Novo Nucleotide Synthesis as a Mediator of Radiation Resistance and a Therapeutic Target in Glioblastoma (5K08CA234416-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9976480. Licensed CC0.

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