De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma

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.

 

Comments:

Your work focuses on identifying alternative treatment strategies for aggressive glioma, specifically targeting mutations affecting isocitrate dehydrogenase (IDH) enzymes. Mutant IDH inhibitors have shown effectiveness against leukemia but have limited activity in aggressive glioma. Through a chemical synthetic lethality screen, you discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH).

Using a genetically engineered mouse model of mutant IDH1-driven astrocytoma and multiple patient-derived models, you demonstrated that the brain-penetrant DHODH inhibitor BAY 2402234 exhibits efficacy as a monotherapy against IDH-mutant gliomas. This efficacy stems from the reliance of glioma cells on the de novo pyrimidine synthesis pathway and the ability of mutant IDH to sensitize cells to DNA damage in the presence of nucleotide pool imbalance.

Your findings present a tumor-selective, biomarker-guided therapeutic strategy that holds promise for clinical translation. By targeting the specific vulnerabilities of IDH-mutant gliomas, such as their reliance on pyrimidine nucleotide synthesis, this approach may offer an effective treatment option for patients with aggressive glioma.

Related Products

Cat.No.	Product Name	Information
S8847	Orludodstat (BAY 2402234)	Orludodstat (BAY 2402234) is a novel and selective dihydroorotate dehydrogenase (DHODH) inhibitor with an IC50 of 1.2 nM.

Related Targets

Dehydrogenase