A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma

Area of Science:

• Oncology
• Metabolic Pathways
• Cancer Genetics

Background:

• Diffuse midline glioma (DMG) is a fatal pediatric cancer driven by oncohistones, presenting challenges for drug development.
• Identifying novel therapeutic targets is crucial for improving outcomes in DMG patients.

Purpose of the Study:

• To identify druggable targets for diffuse midline glioma (DMG).
• To investigate the role of pyrimidine biosynthesis in DMG pathogenesis and explore therapeutic strategies targeting this pathway.

Main Methods:

• Conducted a genome-wide CRISPR screen to identify DMG-specific dependencies.
• Utilized a clinical-stage dihydroorotate dehydrogenase (DHODH) inhibitor (BAY2402234).
• Employed Matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy imaging to assess drug distribution and target engagement in vivo.

Main Results:

• A genome-wide CRISPR screen revealed a selective dependency of DMG on the de novo pyrimidine biosynthesis pathway.
• DHODH inhibition diminished uridine-5'-phosphate (UMP) pools, induced DNA damage, and triggered apoptosis by suppressing replication forks.
• BAY2402234 demonstrated therapeutic concentrations in the brain, suppressed de novo pyrimidine biosynthesis in vivo, and prolonged survival in preclinical DMG models.

Conclusions:

• Targeting the de novo pyrimidine biosynthesis pathway represents a promising therapeutic strategy for diffuse midline glioma (DMG).
• The DHODH inhibitor BAY2402234 shows significant potential as a novel therapy for pediatric DMG, warranting further clinical investigation.