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Updated: Aug 31, 2025
A Protocol for Explant Cultures of IDH1-mutant Diffuse Low-grade Gliomas
Published on: May 9, 2025
De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma
Diana D Shi1, Milan R Savani2, Michael M Levitt3
1Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA 02215, USA; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Abstract:
Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH's ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.
Insights
Targeting dihydroorotate dehydrogenase (DHODH) offers a new strategy for IDH-mutant gliomas. This approach exploits cancer cell dependence on pyrimidine synthesis, showing promise for treating aggressive brain tumors.
Area of Science:
- Oncology
- Biochemistry
- Genetics
Background:
- Isocitrate dehydrogenase (IDH) mutations are common in cancers like glioma and leukemia.
- Current IDH inhibitors show limited efficacy in aggressive gliomas, necessitating novel therapeutic strategies.
- Glioma cells with IDH mutations present a unique vulnerability that can be exploited for targeted therapy.
Purpose of the Study:
- To identify novel therapeutic targets for IDH-mutant gliomas.
- To investigate the potential of targeting the de novo pyrimidine nucleotide synthesis pathway in IDH-mutant glioma.
- To evaluate the efficacy of a brain-penetrant dihydroorotate dehydrogenase (DHODH) inhibitor in preclinical models of IDH-mutant glioma.
Main Methods:
- Conducted a chemical synthetic lethality screen to identify drug sensitivities in IDH1-mutant glioma cells.
- Developed and utilized a genetically engineered mouse model of IDH1-mutant astrocytoma.
- Tested the efficacy of the DHODH inhibitor BAY 2402234 in patient-derived glioma models and the engineered mouse model.
Main Results:
- IDH1-mutant glioma cells are hypersensitive to inhibitors of the de novo pyrimidine nucleotide synthesis pathway, including DHODH.
- The DHODH inhibitor BAY 2402234 demonstrated monotherapy efficacy against IDH-mutant gliomas in preclinical models.
- Mechanistic studies revealed an obligate dependence of glioma cells on de novo pyrimidine synthesis and IDH mutation-induced sensitization to nucleotide pool imbalance.
Conclusions:
- Targeting DHODH represents a promising synthetic lethality strategy for IDH-mutant gliomas.
- BAY 2402234 is an effective monotherapy for IDH-mutant gliomas, supported by preclinical data.
- This biomarker-guided approach targeting pyrimidine synthesis is suitable for clinical translation in glioma treatment.
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