MYCN amplification

This review summarizes RB pathogenesis, including RB1 loss, MYCN amplification, epigenetic dysregulation (e.g., METTL3-mediated m6A), and dysregulated pathways (PI3K/AKT/mTOR, Hedgehog), and highlights CRISPR-engineered organoids for identifying cone precursors as tumor origins and validating therapies (CDK4/6 inhibitors and sunitinib)...Future efforts should integrate multiomics, refine vascularization via 3D bioprinting, and develop immunocompetent models to address the disparity between preclinical research and clinical application. Organoid technology has the potential to advance personalized therapies and ultimately enhance the survival and quality of life of patients with RB worldwide.

P1/2, N=174, Active, not recruiting, Monte Rosa Therapeutics, Inc | Recruiting --> Active, not recruiting

It eliminates both non-MYCN-amplified (SH-SY5Y and SK-N-SH) and MYCN-amplified (SMS-KCNR) NB cells that exhibit PMA-inducible CCL2 expression but not MYCN-amplified NB cells (IMR-32 and NB-1) that exhibit CCL2 repression, and is offset by reciprocal NB cell-induced Fas-mediated Jurkat cell apoptosis. These findings form a solid foundation for further pre-clinical development aimed at identifying clinically relevant physiological immune cell equivalents and alternative PKC activators, with the ultimate goal of translating this mechanism into an effective immune-therapeutic approach for the treatment of high-risk non-immunogenic NBs, especially NBs that exhibit CCL2 and TrkAIII expression.

Leveraging this property, neuroblastoma-derived exosomes can be purified, modified, and loaded with small interfering RNA (siRNA) to silence MYCN expression, combined with chloroquine-an FDA-approved autophagy inhibitor-to simultaneously inhibit autophagy and induce apoptotic signaling...Collectively, exosome-based strategies represent a paradigm shift in formulating combination therapies, offering a multifaceted approach to target MYCN amplification, inhibit autophagy, induce apoptosis, and modulate the tumor-microbiome axis. These innovations hold significant promise for improving clinical outcomes in high-risk MYCN-amplified neuroblastoma patients.

In selected patients, multiplexed biomarkers indicated divergent dynamics, suggesting individual tumor clones differ in their ability to disseminate to the bone marrow and escape therapy. Our pilot data support integrating multiplexed MRD detection in co-clinical trials to monitor the molecular remission state during therapy and follow-up.

This study demonstrates that the Curie score derived from 123I-MIBG SPECT/CT imaging after induction therapy is strongly associated with the prognosis of pediatric patients with MIBG-avid stage 4 high-risk neuroblastoma. Notably, patients achieving a Curie score of 6 or lower after induction therapy may benefit from subsequent consolidation and maintenance treatment strategies.

The presence of diffuse systemic metastasis, axial bone involvement, or skull metastasis is strongly associated with poorer prognosis in pediatric patients with high-risk stage 4 neuroblastoma. Furthermore, axial bone metastasis, diffuse bone metastasis, Curie score>2, MYCN amplification, and 11q23 deletion constitute independent predictors of unfavorable clinical outcomes.

Treatment with DT-061 combined with its inactive competitive antagonist, DT-766, and the proteasome inhibitor, MG-132, reversed this effect on the loss of N-Myc protein expression, suggesting that PP2A-B56α modulation affects N-Myc stability via the proteasomal degradation pathway. In a xenograft model, we observed tumor growth inhibition upon DT-061 treatment, along with a reduction in N-Myc protein expression in vivo. Combined, these results highlight the importance of the PP2A tumor suppressor in regulating MYCN oncogenic signaling and open new potential treatment regimens for high-risk neuroblastoma patients.

Continued progress will depend on integrating molecular profiling into clinical decision-making, refining risk-adapted treatment strategies, and expanding international collaborative research efforts. This narrative review summarizes current knowledge on neuroblastoma epidemiology, biology, staging, and treatment, highlighting recent advances and future directions aimed at improving outcomes for affected children.

Patients with relapsed HR-NBL have poor outcomes with median OS < 2 years. Time to relapse was a significant predictor of OS.

P1, N=26, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed

This study uncovered a novel oncogenic axis in neuroblastoma, where NeuroD1 transcriptionally upregulates USP1, promoting N-Myc stabilization and tumor progression. Furthermore, the findings highlight the therapeutic potential of repurposing Pimozide as a promising treatment strategy for this aggressive tumor subtype.