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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 3

Brequinar inhibits MYC target gene expression and induces ADRN/MES transitions in vivo.

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Brequinar inhibits MYC target gene expression and induces ADRN/MES trans...
(A) Normalized enrichment scores (NESs) of significantly deregulated MYC target genes from gene set enrichment analysis (GSEA) of RNA-Seq data in brequinar-treated xenografts and transgenic mice. Triangles represent tumors 72 hours after 1 dose of brequinar; squares represent tumors 24 hours after 1 dose of brequinar. Gene set names from MSigDB (Hallmarks and CGP) are provided on the x axis. Negative NESs indicate significant downregulation; positive NESs indicate significant upregulation. MYC family target genes are downregulated after brequinar treatment, whereas genes downregulated by MYC increase after brequinar treatment. (B) GSEA enrichment plot demonstrating MYC target gene downregulation (MSigDB Hallmarks MYC target v1 gene set) in brequinar-treated TH-MYCN tumors. NES = –2.63, NOM P = 0.000, FDR q = 0.000. NOM, nominal. (C and D) MTT viability assay (C) and CyQuant proliferation assay (D) in 3 isogenic ADRN (black) and MES (pink) neuroblastoma cell line pairs. (E) Heatmaps showing z scores of significantly deregulated ADRN/MES genes in brequinar-treated xenografts: SK-N-AS at 72 hours; SK-N-BE(2) at 24 hours. (F) Example of increased VIM expression in relapsed SK-N-BE(2)C xenograft tumors following 18 days of brequinar treatment. Image represents maximum intensity projection of a Z-stack. Green color indicates PHOX2B staining (ADRN marker), white color indicates vimentin (VIM) staining (MES marker), and red color indicates MYCN FISH (human neuroblastoma cell marker). Scale bar indicates 20 μm. Red arrow indicates an MES cell (PHOX2B–MYCN+VIM+); white arrow indicates a murine stromal cell (PHOX2B–MYCN–VIM+). (G) Quantification of ADRN/MES transitions in brequinar-treated SK-N-BE(2)C xenografts at 24/72 hours and at relapse. One symbol represents 1 mouse. ADRN, PHOX2B+ VIM–MYCN–; murine, PHOX2B–MYCN–VIM+; MES, PHOX2B–VIM+MYCN+. Numbers of quantified PHOX2B+VIM+ cells per sample are provided in the Methods section.

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