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Neuroblastoma: Advances in Molecular Pathogenesis and Therapy
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Neuroblastoma: Advances in Molecular Pathogenesis and Therapy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 30 September 2026 | Viewed by 1158

Special Issue Editors

Prof. Dr. Paola Fadda

E-Mail Website
Guest Editor
Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09142 Cagliari, Italy
Interests: neuroblastoma; depression; multiple sclerosis; experimental models
Dr. Simona Dedoni

E-Mail Website
Guest Editor
Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09142 Cagliari, Italy
Interests: antidepressants; mood stabilizers; neurotransmitters; neuroplasticity; biomarkers; inflammation and mood disorders; personalized medicine rapid-acting therapeutics; mechanisms of action apigenetic apoptosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neuroblastoma is a paradigmatic pediatric tumor where clinical heterogeneity reflects a complex molecular background. Over the past few years, major advances have been made in defining the molecular pathogenesis of this disease. Beyond classical drivers such as MYCN amplification and ALK mutations, recent studies have highlighted the importance of neurotrophin signaling, epigenetic remodeling, non-coding RNAs, metabolic reprogramming, and tumor–microenvironment interactions as determinants of tumor progression and resistance. These discoveries have reshaped our understanding of neuroblastoma biology and opened new perspectives for therapeutic intervention.

Concurrently, significant progress has been achieved in therapy. Targeted inhibitors against ALK and MYCN pathways, immune-based strategies, including checkpoint blockade and CAR-T cells, as well as differentiation-inducing agents and combinatorial approaches are being actively investigated in both preclinical models and clinical trials. These efforts are moving the field toward precision oncology and more effective treatment paradigms for high-risk patients.

This Special Issue, “Neuroblastoma: Advances in Molecular Pathogenesis and Therapy”, aims to highlight the most recent molecular insights and translational advances that are shaping the future of neuroblastoma research and treatment.

Prof. Dr. Paola Fadda
Dr. Simona Dedoni
Guest Editors

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Keywords

  • neuroblastoma
  • molecular pathogenesis
  • MYCN
  • ALK
  • epigenetics
  • non-coding RNAs
  • tumor microenvironment
  • immunotherapy
  • targeted therapy
  • precision medicine

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Published Papers (2 papers)

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49 pages, 5685 KB  
Article
Quaternary Phosphonium Salts Outperformed Vemurafenib (PLX) and Etoposide Against BRAFV600D,V600E PLX-Resistant Melanoma and MDR Neuroblastoma, Exhibiting No/Low Toxicity on 3T3/HaCaT Cells
by Silvana Alfei, Maria Grazia Signorello, Sara Tirendi, Elaheh Khaledizadeh, Paolo Giordani, Caterina Reggio, Barbara Marengo and Cinzia Domenicotti
Int. J. Mol. Sci. 2026, 27(7), 3170; https://doi.org/10.3390/ijms27073170 - 31 Mar 2026
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Abstract
Late-stage metastatic cutaneous melanoma (MCM) and neuroblastoma (NB) are the most aggressive skin and childhood cancers with survival rates of <50%, mainly due to the emergence of resistance to available drugs, thus requiring an urgent solution. Quaternary phosphonium salts (QPSs) can exhibit strong [...] Read more.
Late-stage metastatic cutaneous melanoma (MCM) and neuroblastoma (NB) are the most aggressive skin and childhood cancers with survival rates of <50%, mainly due to the emergence of resistance to available drugs, thus requiring an urgent solution. Quaternary phosphonium salts (QPSs) can exhibit strong anticancer effects, regardless of the developed resistance. Triphenyl (1) and diphenyl (3 and 4) phosphonium salts were synthesized, treating commercial triphenyl phosphine and synthesizing 11-diphenylphosphanyl-undecan-1-ol (2), respectively, with benzyl bromide. Upon full characterization, they were tested, for the first time, on MeTRAV (BRAFV600D) and MeOV (BRAFV600E) vemurafenib (PLX)-resistant MCM cells, etoposide (ETO)-sensitive (HTLA 230) and multidrug resistant (MDR) (HTLA ER) NB cells, non-tumorigenic human keratinocytes (HaCaT), and mouse embryonic fibroblasts (3T3), as well as red blood cells (RBCs). Viability of MeTRAV cells was decreased to 44.8% by administration of 1 (100 µM), in intermediate-time (48 h) treatments, while short-time exposure (24 h) to 3 (≥75 µM) and 4 (≥50 µM) was sufficient to reduce their viability to 33.6 and 32.2%. Viability of MeOV was decreased under 50% with 5 µM concentrations of 1 and 25 µM of 3 and 4, While cells were exterminated (26.9, 20.6, and 21.8%) with higher concentrations after 48 h exposure. Collectively, 1 was the better performing compound (IC50 = 6.4 µM, 48 h). Viability of HTLA ER cells was decreased under 50% upon 72 h administrations of 1 at concentrations ≥ 50 µM, 48 h (≥75 µM) and 72 h (≥50 µM) of 3, and after 72 h (≥75 µM) of 4, but 72 h exposure and high concentrations of all compounds were necessary for their extermination (31.2, 28.7, and 29.7%). Viability of HTLA 230 cells was not <50% when 1 and 4 were administered for only 24 h, while their viability was <50% after administration of 3 at all times of exposure. At high concentrations, all compounds exterminated cells (33.6, 25.3%, 1, 48–72 h; 38.6, 30.2, and 24.7%, 3, 24–72 h; 33.2%, 4, 72 h). The best-performing compounds were 1 (IC50 = 4.0 µM, HTLA 230) and 3 (IC50 = 27.8 µM, HTLA ER) at 72 h exposure. The cytotoxic effects of compound 4 on MeTRAV cells, when exposed to 24/48 h treatments, were comparable to those of PLX on the same cells in 72 h treatments. Compound 1, in shorter 48 h treatments of PLX-R MeOV, was 2.5-fold more cytotoxic than PLX in 72 h ones. All compounds were not cytotoxic to 3T3 cells at all times of exposure; they had low cytotoxicity to HaCaT cells in 24 and 48 h treatments and were slightly cytotoxic to RBCs in 24 h ones. Compound 1 could be a promising platform to develop new intermediate-time therapies for PLX-R MeOV cells, while 4 could be used to develop 24 and 48 h treatments for PLX-R MeTRAV cells. Also, all compounds could be developed as new treatment options for both ETO-sensitive and MDR late-stage HR-NB cells, being even more effective than ETO by 1.2, 2.0, and 1.3 times (HTLA 230) and 3.2, 4.7, and 3.2 times (HTLA ER). All compounds have the potential to be developed as adjuvants in already existing anticancer cocktails to treat MCM and/or NB. Full article
(This article belongs to the Special Issue Neuroblastoma: Advances in Molecular Pathogenesis and Therapy)
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25 pages, 1187 KB  
Review
Epigenetic Regulation of Trk Receptors and Neurotrophic Signalling in Neuroblastoma: Mechanisms, Plasticity, and Therapeutic Opportunities
by Carlotta Siddi, Jihane Balla, Paola Fadda and Simona Dedoni
Int. J. Mol. Sci. 2026, 27(7), 3238; https://doi.org/10.3390/ijms27073238 - 2 Apr 2026
Viewed by 472
Abstract
Neuroblastoma (NB) represents a paradigmatic developmental malignancy in which lineage specification, oncogenic signalling, and epigenetic regulation converge to define tumour behaviour. Among the molecular axes shaping NB heterogeneity, neurotrophin receptors of the tropomyosin receptor kinase (Trk) family (TrkA, TrkB, and TrkC) and the [...] Read more.
Neuroblastoma (NB) represents a paradigmatic developmental malignancy in which lineage specification, oncogenic signalling, and epigenetic regulation converge to define tumour behaviour. Among the molecular axes shaping NB heterogeneity, neurotrophin receptors of the tropomyosin receptor kinase (Trk) family (TrkA, TrkB, and TrkC) and the p75NTR occupy a central position at the intersection between neuronal differentiation programs and malignant plasticity. While high TrkA and TrkC expression is associated with adrenergic identity, differentiation competence, and favourable clinical outcome, TrkB, frequently sustained by BDNF-driven autocrine loops, characterises mesenchymal-like, therapy-resistant states enriched in metabolic and inflammatory adaptations. Importantly, in NB, the dysregulation of neurotrophin signalling rarely arises from recurrent genetic alterations of neurotrophic tyrosine receptor kinase (NTRK) loci. Instead, Trk receptor expression is dynamically shaped by promoter methylation, polycomb repressive complex 2/Enhancer of Zeste homolog 2 (PRC2/EZH2)-dependent chromatin repression, MYCN-driven transcriptional silencing, enhancer rewiring, and microRNA-mediated control. These epigenetic mechanisms govern reversible transitions along the adrenergic–mesenchymal (ADRN–MES) continuum, enabling tumour cells to adapt to microenvironmental and therapeutic stress. Single-cell and spatial multi-omics approaches have further revealed that Trk-associated phenotypes are embedded within complex regulatory circuits integrating receptor tyrosine kinase (RTK) networks, cytokine signalling, metabolic remodelling, and stromal reinforcement. Here, we provide a comprehensive synthesis of the epigenetic and microenvironmental mechanisms regulating neurotrophin receptors in NB, with particular emphasis on how chromatin plasticity and cell-state transitions reshape Trk-dependent signalling outputs. We discuss advanced three-dimensional and organoid-based models that recapitulate niche-specific regulation of the Trk axis and evaluate emerging therapeutic strategies combining epigenetic modulators, differentiation-inducing agents, and RTK-targeted compounds. Understanding the temporal and spatial dynamics of Trk signalling may open new opportunities to therapeutically stabilise differentiation states and disrupt adaptive resistance programs in high-risk NB. Full article
(This article belongs to the Special Issue Neuroblastoma: Advances in Molecular Pathogenesis and Therapy)
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