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Clin Cancer Res. 2016 May 15;22(10):2470-81. doi: 10.1158/1078-0432.CCR-15-1449. Epub 2015 Dec 2.

Targeting MYCN-Driven Transcription By BET-Bromodomain Inhibition.

Author information

1
Molecular Pharmacology & Chemistry Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany. henssena@mskcc.org.
2
Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany. German Consortium for Translational Cancer Research (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany.
3
Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany.
4
Center of Medical Genetics Ghent (CMGG), Ghent University Hospital, Ghent, Belgium.
5
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Neuroblastoma Genomics, B087, German Cancer Research Center (DKFZ), Heidelberg, Germany.
7
Institute of Pathology, University Hospital Cologne, Cologne, Germany.
8
New Oncology, Köln, Germany. Institut für Hämatopathologie Hamburg, Hamburg, Germany.
9
Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
10
Oncology Therapeutic Development, Clichy, France.
11
Oncology Therapeutic Development, Clichy, France. Oncoethix, Lausanne, Switzerland.
12
Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany. German Consortium for Translational Cancer Research (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany. Neuroblastoma Genomics, B087, German Cancer Research Center (DKFZ), Heidelberg, Germany. Translational Neuro-Oncology, West German Cancer Center (WTZ), University Hospital Essen, University Duisburg-Essen, Essen, Germany. Centre for Medical Biotechnology, University Duisburg-Essen, Essen, Germany.

Abstract

PURPOSE:

Targeting BET proteins was previously shown to have specific antitumoral efficacy against MYCN-amplified neuroblastoma. We here assess the therapeutic efficacy of the BET inhibitor, OTX015, in preclinical neuroblastoma models and extend the knowledge on the role of BRD4 in MYCN-driven neuroblastoma.

EXPERIMENTAL DESIGN:

The efficacy of OTX015 was assessed in in vitro and in vivo models of human and murine MYCN-driven neuroblastoma. To study the effects of BET inhibition in the context of high MYCN levels, MYCN was ectopically expressed in human and murine cells. The effect of OTX015 on BRD4-regulated transcriptional pause release was analyzed using BRD4 and H3K27Ac chromatin immunoprecipitation coupled with DNA sequencing (ChIP-Seq) and gene expression analysis in neuroblastoma cells treated with OTX015 compared with vehicle control.

RESULTS:

OTX015 showed therapeutic efficacy against preclinical MYCN-driven neuroblastoma models. Similar to previously described BET inhibitors, concurrent MYCN repression was observed in OTX015-treated samples. Ectopic MYCN expression, however, did not abrogate effects of OTX015, indicating that MYCN repression is not the only target of BET proteins in neuroblastoma. When MYCN was ectopically expressed, BET inhibition still disrupted MYCN target gene transcription without affecting MYCN expression. We found that BRD4 binds to super-enhancers and MYCN target genes, and that OTX015 specifically disrupts BRD4 binding and transcription of these genes.

CONCLUSIONS:

We show that OTX015 is effective against mouse and human MYCN-driven tumor models and that BRD4 not only targets MYCN, but specifically occupies MYCN target gene enhancers as well as other genes associated with super-enhancers. Clin Cancer Res; 22(10); 2470-81. ©2015 AACR.

PMID:
26631615
DOI:
10.1158/1078-0432.CCR-15-1449
[Indexed for MEDLINE]
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