Project name: DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma [ChIP-seq]

Description: Despite intensive therapy, children with high-risk neuroblastoma are at risk of treatment failure. We applied a multi-omic system approach to evaluate metabolic vulnerabilities in human neuroblastoma. We combined metabolomics, CRISPR screening and transcriptomic data across >700 solid tumor cell lines and identified dihydroorotate dehydrogenase (DHODH), a critical enzyme in pyrimidine synthesis, as a potential treatment target. Of note, DHODH inhibition is currently under clinical investigation in patients with hematologic malignancies. In neuroblastoma, DHODH expression was identified as an independent risk factor for aggressive disease, and high DHODH levels correlated to worse overall and event-free survival. A subset of tumors with the highest DHODH expression was associated with a dismal prognosis, with a 5-year survival of <10%. In xenograft and transgenic neuroblastoma mouse models treated with the DHODH inhibitor brequinar, tumor growth was dramatically reduced, and survival was extended. Furthermore, brequinar treatment was shown to reduce the expression of MYC targets in three different neuroblastoma models in vivo. A combination of brequinar and temozolomide was curative in the majority of transgenic TH-MYCN neuroblastoma mice, indicating a highly active clinical combination therapy. Overall, DHODH inhibition combined with temozolomide has therapeutic potential in neuroblastoma and we propose this combination for clinical testing.Overall design: These samples represent H3K27Ac ChIP-seq of tumor tissue from transgenic TH-MYCN mice treated with the DHODH inhibitor brequinar. Three biological replicates from each experimental condition is included. Mice were treated with brequinar or vehicle, one dose of 50 mg/kg i.p., and tumors were sampled after 72h.

Data type: Epigenomics

Sample scope: Multiisolate

Relevance: ModelOrganism

Last updated: 2022-07-26