TY - JOUR
T1 - DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma
AU - Olsen, Thale Kristin
AU - Dyberg, Cecilia
AU - Embaie, Bethel Tesfai
AU - Alchahin, Adele
AU - Milosevic, Jelena
AU - Ding, Jane
AU - Otte, J. rg
AU - Tümmler, Conny
AU - Myrberg, Ida Hed
AU - Westerhout, Ellen M.
AU - Koster, Jan
AU - Versteeg, Rogier
AU - Ding, Han-Fei
AU - Kogner, Per
AU - Johnsen, John Inge
AU - Sykes, David B.
AU - Baryawno, Ninib
N1 - Funding Information: We would like to thank the core facility for Bioinformatics and Expression Analysis, which is supported by the board of research at the Karolinska Institutet and the research committee at the Karolinska University Hospital. DBS was supported by the Massachusetts General Hospital Transformative Scholars Program. Thank you to Varsha Gandhi and Mary Ayres at the MD Anderson Cancer Center for HPLC measurement of intracellular nucleotides. This research was funded by the Swedish Childhood Cancer Foundation, the Swedish Cancer Society, the Cancer Research Funds of Radiumhemmet (The Cancer Society in Stockholm/the King Gustaf V Jubilee Fund), and the Wenner-Gren foundation. The work in HFD’s laboratory was funded by a grant from the NIH (R01CA236890). Publisher Copyright: © 2022, Olsen et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2022/9/8
Y1 - 2022/9/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85137696752&partnerID=8YFLogxK
U2 - https://doi.org/10.1172/jci.insight.153836
DO - https://doi.org/10.1172/jci.insight.153836
M3 - Article
C2 - 35943801
SN - 2379-3708
VL - 7
JO - JCI Insight
JF - JCI Insight
IS - 17
ER -