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DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma
Thale Kristin Olsen, … , David B. Sykes, Ninib Baryawno
Thale Kristin Olsen, … , David B. Sykes, Ninib Baryawno
Published August 9, 2022
Citation Information: JCI Insight. 2022;7(17):e153836. https://doi.org/10.1172/jci.insight.153836.
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Research Article Oncology Therapeutics

DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma

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Abstract

Despite intensive therapy, children with high-risk neuroblastoma are at risk of treatment failure. We applied a multiomic system approach to evaluate metabolic vulnerabilities in human neuroblastoma. We combined metabolomics, CRISPR screening, and transcriptomic data across more than 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 less than 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 3 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.

Authors

Thale Kristin Olsen, Cecilia Dyberg, Bethel Tesfai Embaie, Adele Alchahin, Jelena Milosevic, Jane Ding, Jörg Otte, Conny Tümmler, Ida Hed Myrberg, Ellen M. Westerhout, Jan Koster, Rogier Versteeg, Han-Fei Ding, Per Kogner, John Inge Johnsen, David B. Sykes, Ninib Baryawno

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Figure 2

DHODH inhibition reduces neuroblastoma growth in vivo.

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DHODH inhibition reduces neuroblastoma growth in vivo.
(A) Genetic and p...
(A) Genetic and pharmacological inhibition of DHODH induces apoptosis in SK-N-BE(2)C but not SK-N-AS cells in vitro. Western blots demonstrate protein expression of DHODH as well as cleaved PARP and activated caspase-3 (apoptosis markers) after shRNA DHODH knockdown and brequinar treatment. (B) Inhibition of DHODH decreases the pool of pyrimidines in neuroblastoma cell lines. UTP (left panel) and CTP (right panel) decay in SK-N-BE(2) and SK-N-AS cells following treatment with brequinar (1 μM). (C) Tumor volumes of SK-N-BE(2) and SK-N-AS NMRI nu/nu xenografts treated with brequinar 50 mg/kg intraperitoneally every 3 days. Tumor volume index at a given day is calculated as the tumor volume relative to the volume at the time of inclusion. Error bars and symbols indicate mean with SD. For each time point, groups are compared with Student’s 2-tailed t test adjusted with Holm-Šidák method. *: P < 0.05; ***: P < 0.001; ****: P < 0.0001. (D) Tumor weight in homozygous TH-MYCN mice 72 hours after receiving 1 dose of either brequinar or vehicle. Error bars show mean with SD. Groups are compared using Student’s 2-sided t test. (E) Kaplan-Meier curve of homozygous TH-MYCN mice treated with brequinar 50 mg/kg intraperitoneally. Treatment started at 32 days of age (marked with dotted line) and continued for 120 days when possible. Groups are compared using log-rank test.

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