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.

Keywords: clinical; neuroblastoma; preclinical; signaling pathway; targeted therapy.

Figure 1

Overview of the molecular signaling pathways implicated in neuroblastoma. The signaling pathways described to play a role in neuroblastoma cells are (1) PI3K/AKT/mTOR pathway—promotes NB cell survival and chemoresistance; (2) Wnt signaling, which is involved in drug resistance, stemness, and increases MYCN levels; (3) p53‐MDM2 pathway, where MDM2 inhibits p53 activity, promotes angiogenesis, increases MYCN translation, and promotes drug resistance. Single nucleotide polymorphisms (i.e., SNP309) and gene amplification increase MDM2 expression. In the p53‐MDM2 pathway, activated p53 is involved in apoptosis and growth arrest; (4) ALK signaling activates PI3K/AKT/mTOR, RAS‐MAPK, and MYCN expression, and an ALK(R1275Q) mutant inhibits the expression of BM‐ and ECM‐associated genes; (5) RAS‐MAPK signaling promotes the survival of neuroblastoma cells and is activated by EGFR signaling; (6) TrkB signaling activates the PIK/AKT/mTOR signaling; (7) MYCN signaling promotes NB cell proliferation and activates MDM2 expression. Gray boxes in the figure represent genetic aberrations (i.e., gene amplification, point mutations, translocations, and deletions) and promoter methylation, and yellow boxes represent downstream biological phenotypes (i.e., survival, chemoresistance, angiogenesis, apoptosis, cell cycle arrest, proliferation, and stemness) in neuroblastoma cells. AKT, protein kinase B; ALK, anaplastic lymphoma kinase; BDNF, brain‐derived neurotrophic factor; BM, basement membrane; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; ERK, extracellular signal‐regulated kinase; FZD1, frizzled‐1; FZD6, Frizzled‐6; HBP1, HMG‐Box transcription factor 1; HIF, hypoxia‐inducible factor; MDR, multidrug resistance; MDM2, mouse double minute 2 homolog; MEK, mitogen‐activated protein; mTOR, mammalian target of rapamycin; NB, neuroblastoma; PI3K, phosphatidylinositol‐3‐kinase; RAS, rat sarcoma; TrKB, tropomyosin receptor kinase B; VEGF, vascular endothelial growth factor [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Targeted therapy involving genetic/protein aberrations in neuroblastoma cells. Some of the approaches employed under targeted therapy involve small molecule inhibitors of TrkB, VEGF, LIN28B, survivin, and Phox2b. Another approach is inhibition of MYCN using one of several strategies: (1) inhibition of MYCN/MAX heterodimerization; (2) inhibition of Aurora A kinase; (3) inhibition of bromodomain and extra‐terminal domain (BET) protein; and (4) inhibition of ODC1. Gray boxes represent inhibitors of survivin, PHOX2B, TrkB, LIN28B, VEGF, AURKA, MYCN/MAX heterodimerization, ODC1, and BET; yellow boxes represent downstream effects, including VEGF, TrkB, and caspase 3 activation. AURKA, Aurora A kinase; BDNF, brain‐derived growth factor; DFMO, difluoromethylornithine; Max, MYC‐associated factor X; MMF, mycophenolate mofetil; ODC, ornithine decarboxylase; Phox2b, paired‐like homeobox 2b; SAHA, suberoylanilide hydroxamic acid; TrKB, tropomyosin receptor kinase B; VEGF, vascular endothelial growth factor [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Targeted therapy in neuroblastoma. Several approaches to targeted therapy involve the following modalities: (1) small molecule inhibitors targeting signaling pathways (i.e., PI3K/AKT/mTOR, RAS‐MAPK, p53‐MDM2, Bcl‐2, and ALK); (2) chemical inhibitors inducing autophagy; (3) immunotherapy employing monoclonal antibodies targeting GD2 and B7‐H3, and using CAR T cells targeting GD2; (4) targeting epigenetic regulators; (5) radiopharmaceuticals targeting NET (¹³¹I‐MIBG) and the somatostatin receptor (DOTATATE); (6) targeted therapy based on topoisomerase inhibitors or nucleoside analogs. Gray boxes represent inhibitors of MEK, ALK, PI3K, AKT, mTOR, Bcl‐2, p53‐MDM2, epigenetic targets, and topoisomerases; compounds that act as autophagy inducers; nucleoside analogs; monoclonal Abs that target B7‐H3 or GD2; and radiopharmaceuticals targeting the somatostatin receptor and NET; yellow boxes represent downstream biological phenotypes (i.e., survival, chemoresistance, apoptosis, cell cycle arrest, and autophagy). AKT, protein kinase B; ALK, anaplastic lymphoma kinase; APAF‐1, apoptotic peptidase activating factor 1; Bax, BCL2‐associated X; Cyt c, cytochrome c; DNMT, DNA methyltransferases; ERK, extracellular signal‐regulated kinase; HAT, histone acetyltransferases; HDAC, histone deacetylases; HMT, histone methyltransferase; MDM2, mouse double minute 2 homolog; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol‐3‐kinase; RAS, rat sarcoma [Color figure can be viewed at wileyonlinelibrary.com]