Direct targeting of oncogenic MYC proteins has been an elusive goal of many cancer drug development efforts. In this issue of Cancer Discovery, Stegmaier and colleagues demonstrate that pharmacologically interfering with the bromodomain and extraterminal (BET) class of proteins potently depletes MYCN in neuroblastoma cells, resulting in cellular cytotoxicity and thus providing a novel approach with a potential impact on a previously undruggable major oncogene.
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| http://dx.doi.org/10.1158/2159-8290.CD-13-0018 | DOI Listing |
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Karolinska Institutet, Stockholm, Stockholm, Sweden.
Transgenic mice and organoid models, such as three-dimensional tumoroid cultures, have emerged as powerful tools for investigating cancer development and targeted therapies. Yet, the extent to which these preclinical models recapitulate the cellular identity of heterogeneous malignancies, like neuroblastoma (NB), remains to be validated. Here, we characterized the transcriptional landscape of TH-MYCN tumors by single-cell RNA sequencing (scRNA-seq) and developed ex vivo tumoroids.
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Departamento de Patología, Universidad de Valencia, Hospital Clínico Universitario de Valencia, CIBERONC (ISCIII Madrid), INCLIVA, Valencia, Spain. Electronic address:
High-risk neuroblastoma continues to show a very high mortality, with a 5-year survival rate of 50%. While MYCN amplification is the main genetic alteration associated with high-risk tumours, other molecular mechanisms, such as alterations in ATRX and TERT, remain poorly understood. ATRX and TERT biomarkers, which are associated with a more aggressive neuroblastoma pattern, should be considered for accurate prognostic stratification.
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The N-Myc transcription factor, encoded by MYCN, is a mechanistically validated, yet challenging, target for neuroblastoma (NB) therapy development. In normal neuronal progenitors, N-Myc undergoes rapid degradation, while, in MYCN-amplified NB cells, Aurora kinase A (Aurora-A) binds to and stabilizes N-Myc, resulting in elevated protein levels. Here, we demonstrate that targeted protein degradation of Aurora-A decreases N-Myc levels.
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Background/aim: Treatment with retinoic acid (RA) often promotes neuroblastoma differentiation and growth inhibition, including the suppression of the expression of the MYCN oncogene. However, RA also targets protumoral chemokines, such as CCL2, which may contribute to the development of resistance. The present study aimed to investigate the regulation and function of CCL2 and N-Myc in RA-treated neuroblastoma cells.
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