PUBLICATION
DHODH Inhibition Suppresses MYC and Inhibits the Growth of Medulloblastoma in a Novel In Vivo Zebrafish Model
- Authors
- Tsea, I., Olsen, T.K., Polychronopoulos, P.A., Tümmler, C., Sykes, D.B., Baryawno, N., Dyberg, C.
- ID
- ZDB-PUB-250109-183
- Date
- 2024
- Source
- Cancers 16(24): (Journal)
- Registered Authors
- Keywords
- DHODH, brequinar, medulloblastoma, paediatric cancers, relapse, targeted therapy
- MeSH Terms
- none
- PubMed
- 39766063 Full text @ Cancers
Citation
Tsea, I., Olsen, T.K., Polychronopoulos, P.A., Tümmler, C., Sykes, D.B., Baryawno, N., Dyberg, C. (2024) DHODH Inhibition Suppresses MYC and Inhibits the Growth of Medulloblastoma in a Novel In Vivo Zebrafish Model. Cancers. 16(24):.
Abstract
Background/objectives Medulloblastoma (MB) is the most common high-grade paediatric brain tumour, with group 3 MB patients having the worst prognosis. A high prevalence of group 3 tumours shows overexpression of the MYC oncogene, making it a potential therapeutic target. However, attempts to directly inhibit MYC have so far demonstrated limited success. Dihydroorotate dehydrogenase (DHODH), a crucial enzyme of the pyrimidine biosynthesis process, has emerged as an up-and-coming target in oncology, as its inhibition has shown promise in several cancers.
Methods In this study, we investigated the efficacy of brequinar, a DHODH inhibitor, in MB, with a focus on group 3. In vitro, BRQ's effects on cell viability and MYC expression were tested in seven MB cell lines. In vivo, a novel zebrafish xenograft model was used to evaluate BRQ's impact on tumour growth and toxicity.
Results High DHODH expression was identified in group 3 and shh MB subgroups, correlating with poor survival and MYC expression. BRQ demonstrated nanomolar efficacy in inducing apoptosis and reducing MYC expression in group 3 MB cell lines. Finally, we established a novel zebrafish xenograft model and demonstrated that BRQ significantly inhibited tumour growth at non-toxic concentrations in vivo, particularly in the D458 metastatic MB cell line.
Conclusions Our findings indicate that DHODH is a promising therapeutic target in group 3 MBs. Furthermore, BRQ shows potential for clinical application, effectively reducing tumour growth and MYC expression in vitro and in vivo. Moreover, our newly established zebrafish xenograft model offers a promising avenue for rapid in vivo drug testing for use in MB.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping