Molecular targeting therapies for neuroblastoma: Progress and challenges

Abstract

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.

NEAT1 as a competing endogenous RNA in tumorigenesis of various cancers: Role, mechanism and therapeutic potential

“…Neuroblastoma (NB) is the most common pediatric solid tumor that arises in the sympathetic nervous system. NB accounts for 7%-8% of childhood malignancies and ~15% of childhood cancer-related deaths [126]. Yang et al explored the mechanism of NEAT1 in NB progression.…”

GLI1: A Therapeutic Target for Cancer

“…Neuroblastoma accounts for roughly 8% of all childhood malignancies and up to 15% of all pediatric cancer deaths ( 152 ). It is a heterogeneous solid tumor, and the heterogeneity is partially driven by the generation of extrachromosomal circular DNA (eccDNA) ( 153 ).…”

Connectivity Map Analysis Indicates PI3K/Akt/mTOR Inhibitors as Potential Anti-Hypoxia Drugs in Neuroblastoma

“…Recent evidence demonstrates that the activation of the PI3K/Akt/mTOR pathway is also implicated in the pathogenesis of NB, and is correlated with tumor progression and a poor prognosis [ 42 , 43 ]. The potential efficacy of inhibiting the PI3K/Akt/mTOR pathway has been observed in NB preclinical studies [ 38 , 44 , 45 , 46 ], and several strategies have been developed to interfere with distinct components of this pathway, showing promises for molecular targeted therapies in advanced stage NB tumors [ 42 , 45 , 47 ].…”