Combination therapies improve the anticancer activities of retinoids in neuroblastoma

Cheung, Belamy B.

doi:10.5306/wjco.v6.i6.212

Cited by 18 publications

(10 citation statements)

References 29 publications

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Section: Discussionmentioning

confidence: 99%

“…Retinoids are an important component of advanced neuroblastoma therapy, yet half of all patients treated with isotretinoin (13-cis retinoic acid) still relapse and die [ 97 ]. Therefore, more effective combination therapies, with a lower side effect profile, are required to improve outcomes [ 97 ]. Our omic data enhance our understanding of RA and MYCN’s antagonistic relationship, revealing the molecular mechanisms through which MYCN inhibits normal RA-mediated neuronal differentiation and suggesting novel combination therapies.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Retinoic acid and TGF-β signalling cooperate to overcome MYCN-induced retinoid resistance

Duffy¹,

Krstić²,

Halász³

et al. 2017

Genome Med

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BackgroundRetinoid therapy is widely employed in clinical oncology to differentiate malignant cells into their more benign counterparts. However, certain high-risk cohorts, such as patients with MYCN-amplified neuroblastoma, are innately resistant to retinoid therapy. Therefore, we employed a precision medicine approach to globally profile the retinoid signalling response and to determine how an excess of cellular MYCN antagonises these signalling events to prevent differentiation and confer resistance.MethodsWe applied RNA sequencing (RNA-seq) and interaction proteomics coupled with network-based systems level analysis to identify targetable vulnerabilities of MYCN-mediated retinoid resistance. We altered MYCN expression levels in a MYCN-inducible neuroblastoma cell line to facilitate or block retinoic acid (RA)-mediated neuronal differentiation. The relevance of differentially expressed genes and transcriptional regulators for neuroblastoma outcome were then confirmed using existing patient microarray datasets.ResultsWe determined the signalling networks through which RA mediates neuroblastoma differentiation and the inhibitory perturbations to these networks upon MYCN overexpression. We revealed opposing regulation of RA and MYCN on a number of differentiation-relevant genes, including LMO4, CYP26A1, ASCL1, RET, FZD7 and DKK1. Furthermore, we revealed a broad network of transcriptional regulators involved in regulating retinoid responsiveness, such as Neurotrophin, PI3K, Wnt and MAPK, and epigenetic signalling. Of these regulators, we functionally confirmed that MYCN-driven inhibition of transforming growth factor beta (TGF-β) signalling is a vulnerable node of the MYCN network and that multiple levels of cross-talk exist between MYCN and TGF-β. Co-targeting of the retinoic acid and TGF-β pathways, through RA and kartogenin (KGN; a TGF-β signalling activating small molecule) combination treatment, induced the loss of viability of MYCN-amplified retinoid-resistant neuroblastoma cells.ConclusionsOur approach provides a powerful precision oncology tool for identifying the driving signalling networks for malignancies not primarily driven by somatic mutations, such as paediatric cancers. By applying global omics approaches to the signalling networks regulating neuroblastoma differentiation and stemness, we have determined the pathways involved in the MYCN-mediated retinoid resistance, with TGF-β signalling being a key regulator. These findings revealed a number of combination treatments likely to improve clinical response to retinoid therapy, including co-treatment with retinoids and KGN, which may prove valuable in the treatment of high-risk MYCN-amplified neuroblastoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0407-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Retinoic acid and TGF-β signalling cooperate to overcome MYCN-induced retinoid resistance

Duffy¹,

Krstić²,

Halász³

et al. 2017

Genome Med

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“…The antitumor activity of FLM and FM in NLF xenografts provided a decrease in tumor growth without significant differences between the two nanomicellar systems during the 4 end of the treatment, on the contrary, FLM gave a progressive tumor disappearance without regrowth while FM produced a delay in the tumor growth up to 15-20 days after the end of treatment, followed by a subsequent regrowth ( Figure 6). The superior antitumor activity of FLM than FM, demonstrated by its ability to completely inhibit the tumor growth, may be due to the antiangiogenic effect of lenalidomide, which, decreasing blood and oxygen supply to the tumor, increases the antitumor effect of fenretinide.…”

Section: Dovepressmentioning

confidence: 99%

<p>Nanomicellar Lenalidomide–Fenretinide Combination Suppresses Tumor Growth in an <em>MYCN</em> Amplified Neuroblastoma Tumor</p>

Orienti

Farruggia

Nguyen

et al. 2020

IJN

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In a previous study, we demonstrated that the combination of fenretinide with lenalidomide, administered by a novel nanomicellar formulation (FLM), provided a strong antitumor effect in a neuroblastoma TrkB-expressing tumor. In this study, we tested the nanomicellar combination in an MYCN amplified neuroblastoma xenograft to assess its efficacy in different tumor genotypes and evaluate the interactions of the nanomicelles with the tumor cells. Experimental Design: FLM was administered to mice bearing human NLF xenografts to evaluate its efficacy in comparison with the nanomicelles containing fenretinide alone (FM). Confocal laser-scanning fluorescence microscopy images of the NLF cells treated with FLM and FM allowed us to estimate the nanomicelle ability to transport the encapsulated drugs inside the tumor cells. Flow cytometric analysis of the cells from treated tumors was performed to assess the effect of treatment on GD2 expression and NK cell infiltration. Results: FLM and FM decreased the growth of NLF xenografts at comparable extents during the treatment period. Afterwards, FLM induced a progressive tumor regression without regrowth, while FM treatment was followed by regrowth within 15-20 days after the end of treatment. Both FLM and FM were able to penetrate the tumor cells transporting the encapsulated drugs. FLM transported higher amount of fenretinide inside the cells. Also, FLM treatment strongly increased GD2 expression in treated tumors and slightly decreased the NK infiltration compared to FM. Conclusion: FLM treatment induced a superior antitumor response than FM in NLF xenografts, presumably due to the combined effects of fenretinide cytotoxicity and lenalidomide antiangiogenic activity. The ability of FLM to penetrate tumor cells, transporting the encapsulated drugs, substantially improved the therapeutic efficiency of this system. Moreover, the enhancement of GD2 expression in FLM treated tumors offers the possibility to further increase the antitumor effect by the use of anti-GD2 CART cells and anti-GD2 antibodies in combination with FLM in multimodal therapies.

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“…The reduced migration and invasion of cancer cell lines induced by retinoids correlate in animal models with decreased tumor growth and metastases (Tabata et al, 2009;Zhao et al, 2009;Benelli et al, 2010;Applegate and Lane, 2015;Waters et al, 2015;Williams et al, 2018). These effects together with other beneficial actions have motivated the use of retinoids for the treatment of several malignancies, including acute promyelocytic leukemia (Cicconi et al, 2018;Lengfelder et al, 2018), head and neck squamous cell carcinoma (Bhatia et al, 2017), and neuroblastoma (Cheung, 2015).…”

Section: Downloaded Frommentioning

confidence: 99%

All-Trans Retinoic Acid Inhibits Migration and Invasiveness of Rheumatoid Fibroblast-Like Synoviocytes

Mosquera

Rodríguez-Trillo

Blanco

et al. 2019

J Pharmacol Exp Ther

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Fibroblast-like synoviocytes (FLSs) are pivotal in inflammation and joint damage of rheumatoid arthritis (RA). They acquire an active and aggressive phenotype, displaying increased migration and invasiveness and contributing to perpetuate synovial inflammation and destruction of cartilage and bone. The main current therapies of RA are focused against inflammatory factors and immune cells; however, a significant percentage of patients do not successfully respond. Combined treatments with drugs that control inflammation and that reverse the pathogenic phenotype of FLS could improve the prognosis of these patients. An unexplored area includes the retinoic acid, the main biologic retinoid, which is a candidate drug for many diseases but has reached clinical use only for a few. Here, we explored the effect of all-trans retinoic acid (ATRA) on the aggressive phenotype of FLS from patients with RA. RA FLSs were treated with ATRA, tumor necrosis factor (TNF), or TNF1ATRA, and cell migration and invasion were analyzed. In addition, a microarray analysis of expression, followed by gene-set analysis and quantitative polymerase chain reaction validation, was performed. We showed that ATRA induced a notable decrease in FLS migration and invasion that was accompanied by complex changes in gene expression. At supraphysiological doses, many of these effects were overridden or reverted by the concomitant presence of TNF. In conclusion, these results have demonstrated the therapeutic potential of retinoic acid on RA FLS provided TNF could be counterbalanced, either with high ATRA doses or with TNF inhibitors.

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Combination therapies improve the anticancer activities of retinoids in neuroblastoma

Cited by 18 publications

References 29 publications

Retinoic acid and TGF-β signalling cooperate to overcome MYCN-induced retinoid resistance

Retinoic acid and TGF-β signalling cooperate to overcome MYCN-induced retinoid resistance

<p>Nanomicellar Lenalidomide–Fenretinide Combination Suppresses Tumor Growth in an <em>MYCN</em> Amplified Neuroblastoma Tumor</p>

All-Trans Retinoic Acid Inhibits Migration and Invasiveness of Rheumatoid Fibroblast-Like Synoviocytes

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