Oncotarget

Research Papers:

BET bromodomain protein inhibition is a therapeutic option for medulloblastoma

Anton George Henssen, Theresa Thor, Andrea Odersky, Lukas Heukamp, Nicolai El-Hindy, Anneleen Beckers, Frank Slpeleman, Kristina Althoff, Simon Schäfers, Alexander Schramm, Ulrich Sure, Gudrun Fleischhack, Angelika Eggert and Johannes Hubertus Schulte _

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Oncotarget. 2013; 4:2080-2095. https://doi.org/10.18632/oncotarget.1534

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Abstract

Anton Henssen1, Theresa Thor2,4, Andrea Odersky 1, Lukas Heukamp6, Nicolai El-Hindy7, Anneleen Beckers8, Frank Speleman8, Kristina Althoff1, Simon Schäfers1, Alexander Schramm1, Ulrich Sure7, Gudrun Fleischhack1, Angelika Eggert9, Johannes H. Schulte1,5

1 Department of Pediatric Oncology and Hematology, University Children`s Hospital Essen, Essen, Germany

2 German Cancer Consortium (DKTK), Germany

3 Translational Neuro-Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany

4 German Cancer Research Center (DKFZ), Heidelberg, Germany

5 Centre for Medical Biotechnology, University Duisburg-Essen, Essen, Germany

6 Institute of Pathology, University Hospital Cologne, Cologne, Germany

7 Department of Neurosurgery, University of Essen, Essen, Germany

8 Center of Medical Genetics Ghent (CMGG), Ghent University Hospital, Ghent, Belgium

9 Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Germany

Correspondence:

Johannes H. Schulte, email:

Keywords: BET bromodomains, BRD4, MYC, JQ1, pediatric brain tumors, targeted therapy

Received: October 23, 2013 Accepted: October 25, 2013 Published: October 27, 2013

Abstract

Medulloblastoma is the most common malignant brain tumor of childhood, and represents a significant clinical challenge in pediatric oncology, since overall survival currently remains under 70%. Patients with tumors overexpressing MYC or harboring a MYC oncogene amplification have an extremely poor prognosis. Pharmacologically inhibiting MYC expression may, thus, have clinical utility given its pathogenetic role in medulloblastoma. Recent studies using the selective small molecule BET inhibitor, JQ1, have identified BET bromodomain proteins, especially BRD4, as epigenetic regulatory factors for MYC and its targets. Targeting MYC expression by BET inhibition resulted in antitumoral effects in various cancers. Our aim here was to evaluate the efficacy of JQ1 against preclinical models for high-risk MYC-driven medulloblastoma. Treatment of medulloblastoma cell lines with JQ1 significantly reduced cell proliferation and preferentially induced apoptosis in cells expressing high levels of MYC. JQ1 treatment of medulloblastoma cell lines downregulated MYC expression and resulted in a transcriptional deregulation of MYC targets, and also significantly altered expression of genes involved in cell cycle progression and p53 signalling. JQ1 treatment prolonged the survival of mice harboring medulloblastoma xenografts and reduced the tumor burden in these mice. Our preclinical data provide evidence to pursue testing BET inhibitors, such as JQ1, as molecular targeted therapeutic options for patients with high-risk medulloblastomas overexpressing MYC or harboring MYC amplifications.


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