Emerging clinical and research approaches in targeted therapies for high-risk neuroblastoma

Abstract

Neuroblastoma is a pediatric cancer that originates from neural crest cells and is the most common extracranial solid tumor in children under five years of age. While low-risk neuroblastoma often regresses spontaneously, high-risk neuroblastoma poses a significant clinical challenge. Recent advances in understanding neuroblastoma's molecular mechanisms have led to the development of targeted therapies that aim to selectively inhibit specific pathways involved in tumor growth and progression, improving patient outcomes while minimizing side effects. This review provides a comprehensive review of neuroblastoma biology and emerging therapeutic strategies. Key topics include (a) immunotherapies and immunotargets, (b) non-coding RNAs (long non-coding RNA, microRNA, and circular RNA), (c) molecular biomarkers and pathways, and (d) limitations and future directions.

Keywords: clinical and preclinical research; high-risk neuroblastoma; neuroblastoma biology; pediatric cancer; targeted therapy.

Figure 1

Overview of emerging targeted therapeutic approaches for high-risk neuroblastoma (HRNB). This figure highlights emerging targeted therapies for HRNB, including immunotherapies, noncoding RNAs, biomarkers, and dysregulated pathways. These approaches aim to overcome the limitations and toxicities of traditional treatments by offering more precise and effective therapeutic options to improve outcomes for HRNB patients. Created with BioRender.

Figure 2

Dysregulated signaling pathways, genomic, and molecular targets in neuroblastoma. This figure from Zafar et al. (2020) highlights key molecular signaling pathways, genomic targets, and molecular targets implicated in neuroblastoma, emphasizing the complex network of dysregulated pathways, including PI3K/AKT/mTOR, Wnt, p53-MDM2, ALK, RAS-MAPK, TrkB, and MYCN, that drive tumor survival, chemoresistance, and progression. These targets represent potential therapeutic interventions for neuroblastoma treatment. Adapted from Zafar et al., 2021, Medicinal Research Reviews, 41(2):961–1021 with permission from Wiley Periodicals LLC.

Figure 3

CAR-NKT cells infiltrate tumor sites and mediate tumor regression in refractory neuroblastoma patients. Figures 2 and Extended Data Figure 1 from Heczey et al. demonstrate that NKT cells are present at higher frequencies within tumor-infiltrating lymphocytes compared to peripheral blood lymphocytes, with 85.7% of tumor-infiltrating NKT cells expressing CAR-GD2 (B). Panel (C) illustrates the reduction in size of neuroblastoma bone metastasis. Panel (A) depicts the clinical trial design for this study. These findings highlight the therapeutic potential of CAR-NKT cells in treating neuroblastoma tumors and promoting their regression. Adapted from Heczey, A., Courtney, A.N., Montalbano, A., et al. Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma: an interim analysis. Nat Med 26, 1686–1690 (2020).

Figure 4

Preclinical evaluation of GPC2-targeting CAR T cells for neuroblastoma treatment. (A-C) show that GPC2-CAR T cells efficiently home to the tumor microenvironment (TME), expand, and enrich as a cytotoxic effector population, highlighting their potential for targeted tumor eradication. (D, E) compare the performance of GPC2-CAR T cells with GD2-CAR T cells (K666.28H.BBζ), showing superior in vitro cytotoxicity, tumor rechallenge response, and reduced tumor burden in vivo. Adapted from Sun et al., 2023, Journal for ImmunoTherapy of Cancer, 11(1):e005881 with permission from BMJ Specialist Journals.

Figure 5

miRNA-29 demonstrates anti-tumor activity by inhibiting cell growth, colony formation, and reducing tumor size and area. (A, B) show tumor area reduction following miR-29 transfection in vivo. (C) depicts the inhibition of various neuroblastoma cell lines in vitro after treatment with miR-29. Adapted from Pathania et al., 2024, Cell Death & Disease, 15 (6):428 with permission from Springer Nature.