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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 4

Combinations of brequinar and temozolomide are synergistic in vitro and have curative potential in vivo.

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Combinations of brequinar and temozolomide are synergistic in vitro and ...
(A and B) Synergy scores of temozolomide and brequinar combinations in SK-N-AS (A) and SK-N-BE(2) (B) cells treated with both drugs. Scores are based on 3 independent experiments. Red color indicates synergy. ZIP scores are shown as 3D (A) and 2D (B) representations. ZIP scores indicate the average percentage excess response due to drug interactions. (C) Overall survival of homozygous TH-MYCN mice treated with either temozolomide alone (n = 7) or a combination of brequinar and temozolomide (n = 7). For comparison, control mice (shown in black) are the same as in Figure 2E. Groups are compared using log-rank test. (D) Immunostainings at original magnification 40× of PHOX2B (white), the apoptosis marker active caspase-3 (red), and the proliferation marker Ki67 (red) in TH-MYCN tumors treated with 1 dose of brequinar and/or temozolomide, sampled 24 hours after the last dose. Nuclei were counterstained with DAPI (blue). Scale bar indicates 40 μm.

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