MYCN Drives a Tumor Immunosuppressive Environment Which Impacts Survival in Neuroblastoma

Raieli, Salvatore; Renzo, Daniele Di; Lampis, Silvia; Amadesi, Camilla; Montemurro, Luca; Pession, Andrea; Hrelia, Patrizia; Fischer, Matthias; Tonelli, Roberto

doi:10.3389/fonc.2021.625207

Cited by 32 publications

(31 citation statements)

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“…MYCN is a key driver of the disease and its overexpression reprograms neuroblastoma cells towards a stem-like phenotype that affects proliferation and cell growth, metabolism, and apoptosis inhibition. It also favors immune escape, invasion, and metastases [ 6 – 8 ].…”

Section: Introductionmentioning

confidence: 99%

The MYCN inhibitor BGA002 restores the retinoic acid response leading to differentiation or apoptosis by the mTOR block in MYCN-amplified neuroblastoma

Lampis

Raieli

Montemurro

et al. 2022

J Exp Clin Cancer Res

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Background Neuroblastoma is a deadly childhood cancer, and MYCN-amplified neuroblastoma (MNA-NB) patients have the worst prognoses and are therapy-resistant. While retinoic acid (RA) is beneficial for some neuroblastoma patients, the cause of RA resistance is unknown. Thus, there remains a need for new therapies to treat neuroblastoma. Here we explored the possibility of combining a MYCN-specific antigene oligonucleotide BGA002 and RA as therapeutic approach to restore sensitivity to RA in NB. Methods By molecular and cellular biology techniques, we assessed the combined effect of the two compounds in NB cell lines and in a xenograft mouse model MNA-NB. Results We found that MYCN-specific inhibition by BGA002 in combination with RA (BGA002-RA) act synergistically and overcame resistance in NB cell lines. BGA002-RA also reactivated neuron differentiation (or led to apoptosis) and inhibited invasiveness capacity in MNA-NB. Moreover, we found that neuroblastoma had the highest level of mRNA expression of mTOR pathway genes, and that BGA002 led to mTOR pathway inhibition followed by autophagy reactivation in MNA-NB cells, which was strengthened by BGA002-RA. BGA002-RA in vivo treatment also eliminated tumor vascularization in a MNA-NB mouse model and significantly increased survival. Conclusion Taken together, MYCN modulation mediates the therapeutic efficacy of RA and the development of RA resistance in MNA-NB. Furthermore, by targeting MYCN, a cancer-specific mTOR pathway inhibition occurs only in MNA-NB, thus avoiding the side effects of targeting mTOR in normal cells. These findings warrant clinical testing of BGA002-RA as a strategy for overcoming RA resistance in MNA-NB.

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Section: Introductionmentioning

confidence: 99%

The MYCN inhibitor BGA002 restores the retinoic acid response leading to differentiation or apoptosis by the mTOR block in MYCN-amplified neuroblastoma

Lampis

Raieli

Montemurro

et al. 2022

J Exp Clin Cancer Res

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“…Lymphoid progenitor cells and B cells were also shown to play roles in the progression of other tumors (27,28). Higher levels of interferon (IFN)-γ-expressing CD4+ T (Th1) cells in patients with cancer have been associated with better prognosis, suggesting that Th1 cells are involved in controlling tumor regression (29)(30)(31). The elevated numbers of CD4 + Th1 T-cells in the high-risk group in the present study suggest that these cells do not play a protective role in NB.…”

Section: Discussionmentioning

confidence: 54%

“…Th1 cells polarize macrophages toward the M1 phenotype, whereas Th2 cells polarize macrophages toward the M2 phenotype. Evaluation of macrophage phenotype enrichment in NB showed that M1 macrophages are signi cantly enriched in NBs without MYCN ampli cation, whereas M2 macrophages are more abundant in NBs with MYCN ampli cation (31). CD56 NK cells are dysfunctional and prevalent in higher-stage tumors and correlate inversely with survival of melanoma patients (32,33).…”

Section: Discussionmentioning

confidence: 99%

Potential effects of POLR2H and DYNC1I2 on the immunity and prognosis of neuroblastoma

et al. 2022

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Objective: The present study utilized bioinformatics techniques and data from the GEO, TARGET, and ArrayExpress databases to compare gene expression in INSS4 and INSS1 neuroblastomas (NBs), thereby identifying metabolites with different levels of expression and predicting the prognosis of patients with NB.METHODS: Genes of patients with INSS4 and INSS1 NBs from the GEO database were screened, with those having | log2fold change (FC) | >3 and adjusted P <0.05 defined as being differentially expressed. These differentially expressed genes (DEGs) were screened to obtain clinical data and RNA sequence datasets from NB patients in the TARGET database. Univariate Cox proportional hazards regression analysis identified prognosis-related genes, which were incorporated into a prognosis model. Based on median risk scores, these patients were divided into high and low-risk groups. Their survival rates were compared, and ROC curves were used to analyze predictive values for NB. NB patients were also divided into two clusters by consensus clustering based on levels of POLR2H and DYNC1I2 expression. Immune infiltration analyses were performed using GSEA, ESTIMATE, CIBERSORT, and ssGSEA. Tumor tissue of 17 NB patients was used for experimental verification and their survival was compared.Result: Analysis of three datasets identified 62 up-regulated genes and 163 down-regulated genes. The prognostic model predicted that the areas under the 3-year and 5-year survival curves were 0.786 and 0.817, respectively. Levels of expression of POLR2H and DYNC1I2 accounted for the highest percentage of risk scores and were included in follow-up analysis. Samples were consistently clustered according to their expression matrix. POLR2H was more highly expressed in cluster 2, whereas DYNC1I2 was more highly expressed in cluster 1. The survival rate of cluster 1 was significantly higher than that of cluster 2. Experimental verification in 17 NB patients showed that these patients could also be divided into two groups, which differed significantly in mortality hazard ratio (HR 9.37 P<0.05).Conclusion: The expression of POLR2H and DYNC1I2 affects the immune microenvironment of NB and can affect patient prognosis. These factors can be used to refine clinical groupings, guide personalized treatment, and suggest new methods for the diagnosis and treatment of NB.

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“…BGA002 showed a specific, dose-dependent decrease in the MYCN mRNA and protein, while decreasing the viability in a panel of 20 NB cell lines, followed by the block of different MYCN tumorigenic alterations, and to the anti-tumor efficacy of BGA002 in vivo in a MNA NB mouse model [ 55 ]. Moreover, while MYCN drives a tumor immunosuppressive environment, which impacts survival in several MYCN-positive tumors, the block of MYCN by the anti-MYCN BGA002 is able to reactivate and restore the effectiveness of the natural killer immune cells against NB [ 56 ]. It has been also found that BGA002 restores the retinoic acid (RA) response, leading to a differentiation or apoptosis in the MNA NB and also to a significant increase in survival in a mouse model of MNA-NB [ 57 ].…”

Section: Oligonucleotide Therapeutics As New Targeted Anti-cancer Dru...mentioning

confidence: 99%

Precision Anti-Cancer Medicines by Oligonucleotide Therapeutics in Clinical Research Targeting Undruggable Proteins and Non-Coding RNAs

et al. 2022

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Cancer incidence and mortality continue to increase, while the conventional chemotherapeutic drugs confer limited efficacy and relevant toxic side effects. Novel strategies are urgently needed for more effective and safe therapeutics in oncology. However, a large number of proteins are considered undruggable by conventional drugs, such as the small molecules. Moreover, the mRNA itself retains oncological functions, and its targeting offers the double advantage of blocking the tumorigenic activities of the mRNA and the translation into protein. Finally, a large family of non-coding RNAs (ncRNAs) has recently emerged that are also dysregulated in cancer, but they could not be targeted by drugs directed against the proteins. In this context, this review describes how the oligonucleotide therapeutics targeting RNA or DNA sequences, are emerging as a new class of drugs, able to tackle the limitations described above. Numerous clinical trials are evaluating oligonucleotides for tumor treatment, and in the next few years some of them are expected to reach the market. We describe the oligonucleotide therapeutics targeting undruggable proteins (focusing on the most relevant, such as those originating from the MYC and RAS gene families), and for ncRNAs, in particular on those that are under clinical trial evaluation in oncology. We highlight the challenges and solutions for the clinical success of oligonucleotide therapeutics, with particular emphasis on the peculiar challenges that render it arduous to treat tumors, such as heterogeneity and the high mutation rate. In the review are presented these and other advantages offered by the oligonucleotide as an emerging class of biotherapeutics for a new era of precision anti-cancer medicine.

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MYCN Drives a Tumor Immunosuppressive Environment Which Impacts Survival in Neuroblastoma

Cited by 32 publications

References 68 publications

The MYCN inhibitor BGA002 restores the retinoic acid response leading to differentiation or apoptosis by the mTOR block in MYCN-amplified neuroblastoma

The MYCN inhibitor BGA002 restores the retinoic acid response leading to differentiation or apoptosis by the mTOR block in MYCN-amplified neuroblastoma

Potential effects of POLR2H and DYNC1I2 on the immunity and prognosis of neuroblastoma

Precision Anti-Cancer Medicines by Oligonucleotide Therapeutics in Clinical Research Targeting Undruggable Proteins and Non-Coding RNAs

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