# Exploiting Pyrimidine Nucleotide Synthesis Dependence for IDH Mutant Glioma Therapy

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $375,150

## Abstract

PROJECT SUMMARY
Gliomas represent 80% of the 26,000 newly diagnosed cases of malignant brain and central nervous system
tumors in the United States each year and are among the most lethal and treatment-resistant human cancers.
Although there is a dire need for new ways to combat this disease, the standard treatment for gliomas has not
changed since 2005 and no new glioma medical therapies have been approved in the last decade. In response
to this challenge, we have devised a new way to treat gliomas that have a mutation in a gene called IDH1. IDH1
mutations are present in 70-90% of lower grade gliomas and secondary glioblastomas, a highly aggressive
subtype of glioma. We surveyed hundreds of drugs and discovered that a class of drugs that inhibit a particular
metabolic pathway preferentially killed brain tumor cells with IDH1 mutations. Our proposal builds on this
discovery by addressing three Specific Aims. Specific Aim #1 is to understand the molecular mechanisms
through which IDH1 mutations increase sensitivity to inhibitors of this metabolic pathway. We will use cultured
brain tumor cell lines that harbor or lack IDH1 mutations to test our hypothesis that the combined effects of IDH1
mutations and these inhibitors severely impair protein processing and lipid production in tumor cells, creating
stress that ultimately triggers cell death. Specific Aim #2 is to use organoid models derived from human glioma
tissue to assess whether the presence of an IDH1 mutation successfully predicts response to inhibitors of the
metabolic pathway we propose targeting. Organoids represent powerful preclinical disease models because they
allow us to test new therapeutic strategies in a cellular system that accurately reflects the makeup of human
brain tumors. Specific Aim #3 is to use a mouse model of glioma to assess whether inhibiting the metabolic
pathway we've identified to be important for IDH1 mutant brain tumor cells leads to desirable therapeutic
responses, including a block in tumor growth and extension of host survival. These studies will clarify whether
targeting this pathway is likely to provide benefit for human patients with IDH1 mutated brain tumors. Taken
together, our work will outline and test a new treatment strategy for brain tumor patients that could be rapidly
translated to the clinic if our studies are successful. Furthermore, our efforts may demonstrate that IDH1
mutations can be used to faithfully identify individuals whose tumors are poised to respond to the treatment
strategy we are developing, thereby providing a way to design potential future clinical trials that have the greatest
chance to provide benefit for glioma patients.

## Key facts

- **NIH application ID:** 10402879
- **Project number:** 5R01CA258586-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Kalil G Abdullah
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $375,150
- **Award type:** 5
- **Project period:** 2021-05-07 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10402879

## Citation

> US National Institutes of Health, RePORTER application 10402879, Exploiting Pyrimidine Nucleotide Synthesis Dependence for IDH Mutant Glioma Therapy (5R01CA258586-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10402879. Licensed CC0.

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