From Dr. Sheila Singh,
pediatric neurosurgeon-researcher
McMaster University
I wanted to share with you our recently published Cancer Cell paper, where our CRISPR screens of patient-derived lines found a new, targetable metabolic vulnerability in myc-amplified childhood medulloblastoma. We repurposed a Bayer DHODH inhibitor which is in clinical trials already toward our brain cancer models, and found huge efficacy.. as did two other groups who co-published in Cancer Cell a month before us.. both groups from Harvard, one showing the same efficacy in IDH mutant glioma and the other in DIPG. This trifecta speaks well for highly reproducible data from 3 strong brain cancer research groups!! Cancer Cell followed up with an editorial that featured the collective impact of all 3 papers:
Summary
MYC-driven medulloblastoma (MB) is an aggressive pediatric brain tumorcharacterized by therapy resistance and disease recurrence. Here, we integrated data from unbiased genetic screening and metabolomic profiling to identify multiple cancer-selective metabolic vulnerabilities in MYC-driven MB tumor cells, which are amenable to therapeutic targeting. Among these targets, dihydroorotate dehydrogenase (DHODH), an enzyme that catalyzes de novo pyrimidine biosynthesis, emerged as a favorable candidate for therapeutic targeting. Mechanistically, DHODH inhibition acts on target, leading to uridine metabolite scarcity and hyperlipidemia, accompanied by reduced protein O-GlcNAcylation and c-Myc degradation. Pyrimidine starvation evokes a metabolic stress response that leads to cell-cycle arrest and apoptosis. We further show that an orally available small-molecule DHODH inhibitor demonstrates potent mono-therapeutic efficacy against patient-derived MB xenografts in vivo. The reprogramming of pyrimidine metabolism in MYC-driven medulloblastoma represents an unappreciated therapeutic strategy and a potential new class of treatments with stronger cancer selectivity and fewer neurotoxic sequelae.