DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-10-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.153836 |
| _version_ | 1797634348258689024 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Thale Kristin Olsen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:07:22Z |
| format | Article |
| id | doaj.art-2b75513611ff4f3b9d9eca1d88064b72 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:07:22Z |
| publishDate | 2022-10-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-2b75513611ff4f3b9d9eca1d88064b722023-11-07T16:24:32ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-10-01717DHODH is an independent prognostic marker and potent therapeutic target in neuroblastomaThale Kristin OlsenCecilia DybergBethel Tesfai EmbaieAdele AlchahinJelena MilosevicJane DingJörg OtteConny TümmlerIda Hed MyrbergEllen M. WesterhoutJan KosterRogier VersteegHan-Fei DingPer KognerJohn Inge JohnsenDavid B. SykesNinib BaryawnoDespite 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.https://doi.org/10.1172/jci.insight.153836OncologyTherapeutics |
| spellingShingle | 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 DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma JCI Insight Oncology Therapeutics |
| title | DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma |
| title_full | DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma |
| title_fullStr | DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma |
| title_full_unstemmed | DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma |
| title_short | DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma |
| title_sort | dhodh is an independent prognostic marker and potent therapeutic target in neuroblastoma |
| topic | Oncology Therapeutics |
| url | https://doi.org/10.1172/jci.insight.153836 |
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