MYCN expression

AlphaScreen of a compound library identifies NSC617570 as an efficient inhibitor of PRKCQ-AS1 RNA and MSI2 protein interaction, and NSC617570 reduces BMX expression, ERK protein phosphorylation, neuroblastoma cell proliferation in vitro and tumor progression in mice. The study demonstrates that PRKCQ-AS1 RNA interacts with MSI2 protein to induce neuroblastoma tumorigenesis, and that targeting PRKCQ-AS1 and MSI2 interaction with small molecule compounds is an effective anticancer strategy.

Our work clarifies that the loss of ARID1A, which tightly associates with MYCN amplification, causes reduced inflammatory signaling. This work finds that ARID1A is a critical regulator of inflammatory signaling in NB and provides rationale for testing immune therapies in MYCN amplified NB that are effective in adult ARID1A mutated cancers.

Combined knockdown of Beclin1 and the death receptor CD95 almost abolished the antitumor actions of 602 and 602NR. 602, and more so 602NR, kills MYCN NB cells and interacts with standard-of-care chemotherapeutics to cause further killing via autophagy and death receptor signaling.

Comprehensive analysis of the gene expression profiles revealed that the combination treatment upregulated apoptosis-related pathways and downregulated DNA repair-related pathways. After the combined treatment of CCC-002 and ATR inhibitor, MYCN-amp cells showed less FISH probe signal and mRNA expression of MYCN, which was accompanied by an increase in DNA damage markers in the genomic region of MYCN, highlighting that ATR inhibitors synergize with CCC-002 and play a crucial role in the development of a novel MYCN-targeting therapy for MYCN-amp neuroblastoma.

ACOT2 downregulation by MI202 was associated with reduced MYCN expression, suggesting that ACOT2 may mediate MYCN-driven tumorigenesis through lipid desaturation. Overall, this study presents a robust high-throughput screening platform to identify MYCN inhibitors and highlights the potential of pharmacological downregulation of MYCN as a therapeutic strategy for targeting HCC.

P1, N=26, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Jan 2025 --> Jun 2025 | Trial primary completion date: Jan 2025 --> Jun 2025

Sustained high-dose ω3 (weeks/months) is safe and well-tolerated in humans. These results suggest that ω3 DHA and EPA delivery at ultra-high doses may represent a viable low-toxicity therapy for neuroblastoma.

Mutations in the tyrosine kinase domain of the Anaplastic Lymphoma Kinase (ALK) oncogene in neuroblastoma occur most frequently at one of three hotspot amino acid residues, with the F1174* and F1245* variants conferring de novo resistance to first and second generation ALK inhibitors including crizotinib and ceritinib. Lorlatinib treatment also led to the repression of MYCN expression and its occupancy at promoters of the same G2/M kinases. These data providing mechanistic insight into the superior efficacy of lorlatinib over crizotinib for the treatment of ALK-driven neuroblastoma.

Synergism between CAR T cells and the indirect MYCN inhibitor, MLN8237, was assessed in vitro using the Bliss model and in vivo in an immunocompromised mouse model...We identify target antigen downregulation as source of resistance against L1CAM-CAR T cells in MYCN-driven neuroblastoma cells. These data suggest that L1CAM-CAR T cell therapy combined with pharmacological MYCN inhibition may benefit patients with MYCN-amplified neuroblastoma.

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.

In our study, the in vitro and in vivo experiments confirmed that chidamide and venetoclax synergistically inhibited the expression of MYCN and increased the expression of DKK3 by inhibiting the activity of HDAC and BCL2, inhibiting the Wnt/β-catenin signaling pathway and B-ALL cell proliferation. These findings indicate that the HDACi chidamide and the BCL2 inhibitor venetoclax can be used in combination to treat B-ALL, providing a new method and strategy for treating B-ALL.

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.

Furthermore, it suggests that MYCNOS could serve as a predictor to identify patients who may benefit from NOTCH inhibitors. These findings provide valuable insights for future studies aimed at developing therapeutic strategies targeting these identified pathways.

• 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.

Here, PGV-1 was intended to challenge the growth-suppressing effect on HLF and HuH-6 and trace the molecular target mechanism of action compared to sorafenib...The lower the MYCN expression, the higher the cytotoxic effect of PGV-1. PGV-1 abrogates cell cycle progression of both cells in mitosis through EGFR inhibition and stabilizes PLK-1 and AurA in correlation with the suppression of MYCN expression.

Notably, the si-ELAVL3-transfected NB cells enhanced the anti-tumor activity of NK cells. Collectively, this study offers avenues for predicting the risk stratification of patients with NB and reveals a potential mechanism by which ELAVL3 regulates NB cell death.

Our study demonstrates the utility of adjusting RAS values in discriminating ganglioside metabolism subtypes, highlighting the potential for identifying novel cancer subgroups based on sphingolipid profiles. These findings contribute to a better understanding of ganglioside dysregulation in NT and may have implications for stratification and targeted therapeutic strategies in these tumors and other tumor entities with a deregulated GSL metabolism.

Combined intervention with MIR654/3P mimic and MIR9/3P antagomir had synergistic action on decreasing tumor burden and improving disease outcome. MIR654/3P, as a putative tumor suppressor in EBV- BL, collaborated MIR9/3P might serve as a therapeutic agent to treat EBV- BL patients in combination with existing chemotherapy and immunotherapy regimes.

Blockade of the CD47/SIRPα and PD-1/PD-L1 signaling pathways by the SIRPα-Fc fusion protein IMM01 and monoclonal antibody atezolizumab significantly restored the anti-MM activity of macrophages and T cells in the microenvironment, respectively. Moreover, our study clarified that DNp73 overexpression not only promotes aggressive growth of tumor cells but, more importantly, promotes immune escape of MM cells through upregulation of immune checkpoints. DNp73 could serve as a biomarker for immunotherapy targeting PD-L1 and CD47 blockade in MM patients.

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.

Furthermore, we discovered that pharmacological inhibition of BMP signaling was sufficient to create an aberrant NCC gene signature in SAP cells, phenocopying MYCN overexpression. Together, our results suggest that MYCN overexpression in SAPs disrupts their differentiation by eliciting abnormal NCC gene expression programs, and dampening BMP signaling response, having developmental implications for the priming of NB in vivo.

The HSF1-MYCN axis constitutes a transcription-dependent regulatory mechanism that may function as both a prognostic indicator and a promising therapeutic target in liver cancer. Further exploration of this axis could yield valuable insights into novel treatment strategies for HCC.

Single-cell RNA sequencing of human clinical HGSC samples revealed a strong negative association between cancer cell-intrinsic MYCN transcriptional program and type I IFN signaling. Thus, N-MYC inhibits tumor cell-intrinsic innate immune signaling in HGSC, making it a compelling target for immunotherapy of cold tumors.

Our research demonstrates that KAP1, transcriptionally activated by MYCN, forms a complex with YTHDC1 and METTL3, which in turn maintain the stabilization of MYCN mRNA in an m6A-dependent manner. Targeting m6A modification by STM2457, a small-molecule inhibitor of METTL3, could downregulate MYCN expression and attenuate tumor proliferation. This finding provides a new alternative putative therapeutic strategy for MYCN-amplified NB.

These changes correlate with a stepwise aberration of developmental transcription factor networks. Together, our results sketch a mechanistic framework for the CNA-driven initiation of embryonal tumours.

This study proved the functional significance of LOXL1-AS1 in SHH-MB metastasis by its promotion of TGF-β2-mediated cancer stem-like phenotypes, providing both prognostic and therapeutic potentials for targeting SHH-MB metastasis.

Our results underscore the multifactorial nature of tumor aggressiveness in EPNs of the spinal region. This study enhances our knowledge of the clinical and pathological features of Sp-EPNs and MPEs and highlights the need for better diagnostic and prognostic markers in these rare tumors.

Furthermore, a short-term KDM4 inhibition in combination with conventional, cytotoxic chemotherapy results in complete tumor responses of xenografts with MNA. Thus, KDM4 blockade may serve as a transformative strategy to target the adrenergic CRC dependencies in MNA neuroblastomas.

P1, N=26, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Jan 2024 --> Jul 2024 | Trial primary completion date: Jan 2024 --> Jul 2024

To conclude, MYCN-amplified spinal ependymomas are rare tumors, accounting for ~ 4% of spinal cord ependymomas. Within the limitation of small sample size, MYCN IHC showed excellent concordance with MYCN gene amplification.

P=N/A, N=44, Completed, Masonic Cancer Center, University of Minnesota | Recruiting --> Completed | N=20 --> 44

In conclusion, the inhibition of OCT4 binding at the MYCN locus resulted in reduced MYCN activity, which in turn led to the downregulation of high-ORF dominance transcripts and subsequently induced caspase-2-mediated cell death in MYCN-amplified NB cells. Therefore, disruption of the OCT4 binding at the MYCN locus may serve as an effective therapeutic strategy for MYCN-amplified NB.

Patients with HCC with higher serum MYCN levels after a 4-week treatment of ACR exhibited a significantly higher risk of recurrence (hazard ratio 3.27; p = .022). In conclusion, serum MYCN holds promise for biomarker-based precision medicine for the prevention of HCC, long-term prognosis of early-stage HCC, and identification of high-response subgroups for ACR-based treatment.

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Moreover, genetic knockdown of MTHFD1 or application of the anti-folic acid metabolism drug methotrexate (MTX) potentiated the anti-tumor effect of JQ1 both in vitro and in vivo. Taken together, MTHFD1 as an oncogene is a potential therapeutic target for MYCN-amplified NB. The combination of MTX with JQ1 is of important clinical translational significance for the treatment of patients with MYCN-amplified NB.

Indeed, the PRMT5 inhibitor, JNJ-64619178, reduced cell viability and SNRPD3 methylation in neuroblastoma cells with high SNRPD3 and MYCN expression...Third, this leads to balanced alterative splicing (AS) activitiy that is favorable to neuroblastoma. Together this forms as a therapeutic vulnerability where SNRPD3 perturbation or PRMT5 inhibitors are selectively toxic to neuroblastoma by conditionally disturbing splicing activity.

Tumor uptake of intravenously injected Pt-MYCN-PIP was low and its delivery to tumors should be improved for therapeutic application. The present results provided a potential strategy, targeting the key oncogenes for cancer survival for Auger electron therapy.

Engagement and degradation of XIAP by ARTS mimetics is a novel targeting strategy for neuroblastoma that may be especially effective against MYCN-amplified disease with intrinsically high XIAP expression. First-in-class ARTS mimetic A4 demonstrates preclinical efficacy and warrants further development and study.

Notably, neuroblastoma cells failed to develop significant resistance to the mitoribosomal inhibitor doxycycline over a long-term repeated (pulsed) selection. Collectively, we identify mitochondrial translation machinery as a novel synthetic lethality target for multidrug-resistant MYC-driven tumors.

Prophylactic treatment using antimitotic agents barasertib and vincristine significantly delayed the onset of tumor formation, reduced pre-malignant neuroblast hyperplasia, and prolonged survival in TH-MYCN mice. Moreover, combination therapy with antimitotic compounds and BCL2 inhibitors exploited mitotic stress induced by antimitotics and was synergistically toxic to neuroblastoma cell lines. These results collectively suggest that mitotic dysregulation is a key component of tumorigenesis in early neuroblasts, which can be inhibited by the combination of antimitotic compounds and pro-apoptotic compounds in MYCN-driven neuroblastoma.