Neuroblastoma is a peripheral nervous system tumor that almost exclusively occurs in young children. Although intensified treatment modalities have led to increased patient survival, the prognosis for patients with high-risk disease is still around 50%, signifying neuroblastoma as a leading cause of cancer-related deaths in children. Neuroblastoma is an embryonal tumor and is shaped by its origin from cells within the neural crest. Hence, neuroblastoma usually presents with a low mutational burden and is, in the majority of cases, driven by epigenetically deregulated transcription networks. The recent development of Omic techniques has given us detailed knowledge of neuroblastoma evolution, heterogeneity, and plasticity, as well as intra- and intercellular molecular communication networks within the neuroblastoma microenvironment. Here, we discuss the potential of these recent discoveries with emphasis on new treatment modalities, including immunotherapies which hold promise for better future treatment regimens.

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.