MYCN amplification

We highlight the promising results of the clinical trial involving the combination of adavosertib and irinotecan, which encourages further clinical trials with adavosertib targeting NB with ATRX mutations. Preclinical results with BET inhibitors (OTX015 and AZD5153) and with 6-thio-2'-deoxyguanosine, targeting NB with TERT mutations, are promising. Both represent future therapeutic targets, emphasizing the need to prioritize research using these models.

This is the first reported case of IDEM double primary ependymoma and meningioma, highlighting the rarity of such cases and the importance of thorough diagnostic workup and surgical excision for IDEM tumors. Genetic analysis adds to the understanding of these rare tumors and guides management strategies.

HLB-0532259 surpasses the cellular efficacy of established allosteric Aurora-A inhibitors, exhibits favorable pharmacokinetic properties, and elicits tumor reduction in a murine xenograft NB model. This study broadly delineates a strategy for targeting "undruggable" proteins that are reliant on accessory proteins for cellular stabilization.

P1, N=99, Active, not recruiting, Children's Oncology Group | Trial completion date: Sep 2024 --> Sep 2025

CCL2 and N-Myc promote the viability of RA-treated cells, although the levels of these mediators were not consistently correlated with cellular outcomes, especially during apoptotic signaling.

P=N/A, N=600, Active, not recruiting, Institut Curie | Recruiting --> Active, not recruiting

It follows that alternating between inhibiting MDM2 to restore p53 activity and inhibiting ARF to attenuate p53 activity is a promising, if unorthodox, therapeutic strategy. The multicellular model has the advantages of modularity, high resolution, and scalability, making it a potential foundation for creating digital twins of neuroblastoma patients.

Molecular typing of pediatric spinal ependymomas aids in identifying very high-risk MYCN-amplified ependymomas. Further insights into the molecular heterogeneity of spinal ependymomas are needed for future clinical decision-making.

In summary, we established an in vitro model system to investigate the interaction of RB tumor cells with their TME. Our findings contribute to a better understanding of the relationship between RB tumor malignancy and its TME and will facilitate the development of effective treatment options for eye preserving therapies.

This review aims to capture the most recent studies that investigate metabolic rewiring in MYCN-amplified and MYCN-activated cells from the perspective of alterations to glycolysis, the TCA cycle, and oxidative phosphorylation, in addition to changes to amino acid, nucleotide, and lipid metabolism that can be relevant to therapy. A better understanding of the metabolic profile of MYCN-amplified disease will facilitate the identification of effective treatment options and improve the prognosis of high-risk neuroblastoma patients.

18F-OC could be used in the evaluation of NB, and the modified Curie scoring system could be used to semi-quantify the disease extent of NB in 18F-OC PET/CT.

We investigate the interplay between TERT activation, overexpression and copy-number dosage and reveal loss of imprinting at the RTL1 gene associated with poor clinical outcome. These results highlight the importance of gene dosage in key oncogenic mechanisms in neuroblastoma.

P=N/A, N=7, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

P1, N=26, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting

While dinutuximab beta immunotherapy is an effective and widely used treatment, it has several potential side effects that must be carefully monitored...However, DFMO has adverse effects that require continuous monitoring. Further research is needed to minimize these side effects and improve its efficacy, particularly in addressing resistance caused by long-term use.

The results of this study suggest that CNTN1 is a potential biomarker and therapeutic target in neuroblastoma. Further investigation of CNTN1 could have significant clinical implications for improving neuroblastoma treatment.

PP2A activators decreased NB cell viability, proliferation, and motility. In vivo experiments show that PP2A activators have more significant effects on tumorigenesis in MYCN-amplified tumors. Finally, phosphorylation of MYCN protein was decreased following treatment with novel sulfonamide PP2A activators. These data and mechanistic insights may be useful for developing new PP2A-based therapies that target MYCN for the treatment of NB.

We used a gelatin- and silk fibroin-based hydrogel system with cross-linked vitronectin (VN) as an artificial biomimetic three-dimensional (3D) environment to mirror aggressive neuroblastoma (NB) tumors and tested long-term cell response to Cilengitide (CLG)...Cell detachment and aggregation were maintained in hydrogel-free monolayer cells whereas cells embedded in hydrogels presented different responses to treatment, suggesting differential anoikis resistance between the two cell lines. This underscores the advantages of testing therapeutic approaches using real-time imaging of tumor cells in 3D biomimetic models and its contribution to precision medicine.

Moreover, we demonstrate the functional significance of this alternative route in human cancer cells, revealing a notable association between elevated expression of PRDX6 and human MYCN-amplified neuroblastoma subtype. Our study sheds light on a previously unrecognized aspect of Sec metabolism and its implications in ferroptosis, offering further possibilities for therapeutic exploitation.

Preliminary analysis reveals significant diversity in chromatin landscape and gene expression across neuroblastoma cell lines. This dataset is a valuable resource for studying the transcriptional and epigenetic mechanisms of this deadly childhood disease.

A deep learning model using attention-based multiple instance learning (aMIL) and self-supervised learning (SSL) was developed to perform pathologic classification of neuroblastic tumors and assess MYCN-amplification status using H&E-stained whole slide images from the largest reported cohort to date. The model showed promising performance in identifying diagnostic category, grade, mitosis-karyorrhexis index (MKI), and MYCN-amplification with validation on an external test dataset, suggesting potential for AI-assisted neuroblastoma classification.

• RNA-seq using control RNAs spiked-in on a per-cell basis more accurately reflects global expression changes, when comparing cell populations with substantially different MYCN expression levels. • In MYCN-amplified neuroblastoma, retinoic acid dramatically decreases MYCN expression levels, resulting in large changes in overall RNA expression levels per cell.

In addition, we provide evidence that sustained overexpression of the MYCN oncogene in tNCC drives METTL3 recruitment to a specific subset of genes including posterior HOX genes creating an undifferentiated state. Moreover, METTL3 depletion/inhibition induces DNA damage and differentiation of MYCN overexpressing cells and increases vulnerability to chemotherapeutic drugs in MYCN-amplified patient-derived xenografts (PDX) in vivo, suggesting METTL3 inhibition could be a potential therapeutic approach for NB.

This study provides comprehensive genomic profiling of CPTs, highlighting distinct genetic alterations associated with different histological grades and patient demographics. These findings may inform future research and therapeutic strategies targeting specific molecular pathways in CPTs.

Overall, our data indicate that c-MET directly regulates NB growth and 3D spheroid growth, and c-MET inhibition by tivantinib may be an effective therapeutic approach for high-risk NB. Further developing c-MET targeted therapeutic approaches and combining them with current therapies may pave the way for effectively translating novel therapies for NB and other c-MET-driven cancers.

SHAP analysis highlighted lower sphericity, higher flatness, and greater gray-level heterogeneity as predictive for MYCNampRB1+/+ status, yielding an AUC of 0.81 (SD 0.11). This study shows the potential of MRI-based radiomics to distinguish MYCNampRB1+/+ and RB1-/- retinoblastoma subtypes.

P2, N=41, Active, not recruiting, Children's Oncology Group | Trial completion date: Sep 2024 --> Sep 2025

P=N/A, N=75, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

P2, N=42, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

Patients with neuroblastoma characterized by these genetic characteristics often have suppressed T cell response and an overabundance of immunosuppressive cells and cytokines in the peripheral blood. This imbalance is significantly associated with poor EFS. Moreover, if these patients show an elevated levels of immunosuppressive cytokines such as IL-10, the prognosis will be worse.

The hub genes (VGF, DGKD, and C19orf52) of neuroblastoma are screened. VGF, one of the hub genes, may have a high diagnostic value and is involved in the immune cell infiltration in neuroblastoma tissue, which may be used as a biomarker for the diagnosis of neuroblastoma and provides a new direction for clinical prognosis prediction and management improvement.

High RNF121 mRNA expression associated with poor prognosis in human neuroblastoma tissues and another MYC-driven malignancy, laryngeal cancer. RNF121 is thus an essential oncogenic cofactor for MYCN and a target for drug development.

Adaptable to other proteins of interest, this approach provides valuable insights into neuroblastoma protein synthesis. For complete details on the use and execution of this protocol, please refer to Chittavanich et al.1.

Although MYCN knockdown showed no synergistic effect with PARP inhibitors, fluorescence in situ hybridization and quantitative PCR analyses indicated that PARP inhibitors enhanced the effect of CCC-002 to reduce MYCN copy number and suppress its expression. Overall, our study provides novel insights into a therapeutic approach that combines CCC-002 and PARP inhibition to effectively induce DNA damage and apoptosis in MYCN-amp NB cells.

Here, we present a comprehensive label-free mass spectrometry-based total proteomics and phosphoproteomics dataset (432 raw files with FragPipe search outputs; available on PRIDE with accession number PXD054441) where we identified and quantified 4,907 proteins, 16,744 phosphosites and 5,084 phosphoproteins, derived from NGF/BDNF/NT-3 treated TrkA/B/C-overexpressing neuroblastoma cells with differential MYCN status. Analysing our dataset offers valuable insights into TrkA/B/C receptor signalling in neuroblastoma and its modulation by MYCN status; and holds potential for advancing therapeutic strategies in this challenging childhood cancer.

MYC(N)-amplified MB displays significant clinicobiological heterogeneity. Diagnostics incorporating molecular groups, subgroups, and clinical factors enable their risk assessment. VHR "canonical" MYC tumors are essentially incurable and SHH-MYCN-amplified MBs fare extremely poorly (20% survival at 5 years); both require urgent development of alternative treatment strategies. Conventional risk-adapted therapies are appropriate for more responsive groups, such as noncanonical MYC and non-SHH-MYCN MB.

P1, N=41, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed

Independent of MYCN amplification, inhibitors of RA metabolism or HGF signaling might prevent the emergence of RA-resistant neuroblastoma cells when co-applied with RA.

This strategy, partly adopted in the ongoing SIOPE protocol,confirmed improved EFS and OS over previously reported outcomes in all high-risk categories;SHH tumors appeared the most aggressive.

Here we evaluate the highly selective first-in-class PRMT5 inhibitor GSK3203591 and its in vivo analogue GSK3326593 as targeted therapeutics for MNA neuroblastoma...In vivo efficacy of GSK3326593 is confirmed by increased survival of Th-MYCN mice, with drug treatment triggering splicing events and protein decreases consistent with in vitro data. Together our study demonstrates the PRMT5-dependent spliceosomal vulnerability of MNA neuroblastoma and identifies the epitranscriptome and glutamine metabolism as critical determinants of this sensitivity.

LP-WGS of CSF-derived cfDNA is feasible using a clinical platform, with greater sensitivity for tumor detection compared to conventional CSF cytologic analysis at initial staging. Large prospective studies are needed to further evaluate LP-WGS as a predictive biomarker.

Finally, in co-culture experiments with CD8 + T cells, 9-ING-41 improved immune recognition of the neuroblastoma cells, as evidenced by augmented T-cell activation marker levels and T-cell proliferation, which was further enhanced by PD-1 immune checkpoint inhibition. Our preclinical study provides experimental support to further explore the GSK-3β inhibitor 9-ING-41 as an immunomodulatory agent to increase tumor immune recognition in neuroblastoma.