Neuroblastoma is the most common extracranial solid tumor in children. One subset, high-risk neuroblastoma, is very difficult to treat and requires multi-modal therapy. Intensification of therapy has vastly improved survival rates, and research is focused on novel treatments to further improve survival rates. The current treatment schema is divided into three stages—induction, consolidation, and maintenance. This review serves as an overview of the current treatment for high-risk neuroblastoma and a glimpse at current research for future therapy.

There is an urgent need to identify novel therapies for childhood cancers. Neuroblastoma is the most common pediatric solid tumor, and accounts for ~15% of childhood cancer‐related mortality. Neuroblastomas exhibit genetic, morphological and clinical heterogeneity, which limits the efficacy of existing treatment modalities. Gaining detailed knowledge of the molecular signatures and genetic variations involved in the pathogenesis of neuroblastoma is necessary to develop safer and more effective treatments for this devastating disease. Recent studies with advanced high‐throughput “omics” techniques have revealed numerous genetic/genomic alterations and dysfunctional pathways that drive the onset, growth, progression, and resistance of neuroblastoma to therapy. A variety of molecular signatures are being evaluated to better understand the disease, with many of them being used as targets to develop new treatments for neuroblastoma patients. In this review, we have summarized the contemporary understanding of the molecular pathways and genetic aberrations, such as those in MYCN, BIRC5, PHOX2B, and LIN28B, involved in the pathogenesis of neuroblastoma, and provide a comprehensive overview of the molecular targeted therapies under preclinical and clinical investigations, particularly those targeting ALK signaling, MDM2, PI3K/Akt/mTOR and RAS‐MAPK pathways, as well as epigenetic regulators. We also give insights on the use of combination therapies involving novel agents that target various pathways. Further, we discuss the future directions that would help identify novel targets and therapeutics and improve the currently available therapies, enhancing the treatment outcomes and survival of patients with neuroblastoma.

Gain-of-function mutations in the ALK oncogene occur in 15% or more of newly diagnosed patients with high-risk neuroblastoma. This discovery positioned ALK as the first tractable molecular target for patients with this disease. However, crizotinib showed limited anti-tumor activity in this phase 2 trial for patients with relapsed ALK+ neuroblastoma. The preclinical mechanism underlying this observation revealed that two of the three hot spot mutations in ALK confer intrinsic resistance to crizotinib due to preferential affinity for ATP binding that could potentially be overcome by higher drug exposures. The observed responses occurred in patients with the most common both germline and somatic hot spot mutation at residue R1275.Despite limited activity and lack of objective responses in patients harboring de novo resistant ALK mutations, we conclude that, while this was possibly a limitation of the number of patients enrolled, this is more likely due to an inability to reach the higher concentrations of crizotinib needed to overcome the competing ATP affinity. Emerging data with the third generation ALK inhibitor lorlatinib shows promise for patients with ALK-driven neuroblastoma.