| Autor: |
Olsen TK; Division of Pediatric Oncology and Pediatric Surgery, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden., Dyberg C; Division of Pediatric Oncology and Pediatric Surgery, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden., Embaie BT; Division of Pediatric Oncology and Pediatric Surgery, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden., Alchahin A; Division of Pediatric Oncology and Pediatric Surgery, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden., Milosevic J; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Ding J; Division of Molecular and Cellular Pathology, Department of Pathology, Heersink School of Medicine, the University of Alabama at Birmingham, Birmingham, Alabama, USA., Otte J; Division of Pediatric Oncology and Pediatric Surgery, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden., Tümmler C; Division of Pediatric Oncology and Pediatric Surgery, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden., Hed Myrberg I; Division of Pediatric Oncology and Pediatric Surgery, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden., Westerhout EM; Department of Oncogenomics, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands., Koster J; Department of Oncogenomics, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands., Versteeg R; Department of Oncogenomics, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands., Ding HF; Division of Molecular and Cellular Pathology, Department of Pathology, Heersink School of Medicine, the University of Alabama at Birmingham, Birmingham, Alabama, USA., Kogner P; Division of Pediatric Oncology and Pediatric Surgery, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden., Johnsen JI; Division of Pediatric Oncology and Pediatric Surgery, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden., Sykes DB; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.; Harvard Stem Cell Institute, Cambridge, Massachusetts, USA., Baryawno N; Division of Pediatric Oncology and Pediatric Surgery, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. |
| Abstrakt: |
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. |
