Universität zu Köln

Henssen, Anton ORCID: 0000-0003-1534-778X, Thor, Theresa, Odersky, Andrea, Heukamp, Lukas ORCID: 0000-0002-3388-3482, El-Hindy, Nicolai, Beckers, Anneleen, Slpeleman, Frank, Althoff, Kristina, Schaefers, Simon, Schramm, Alexander ORCID: 0000-0001-7670-7529, Sure, Ulrich, Fleischhack, Gudrun, Eggert, Angelika ORCID: 0000-0003-3476-8184 and Schulte, Johannes Hubertus ORCID: 0000-0003-0671-1201 (2013). BET bromodomain protein inhibition is a therapeutic option for medulloblastoma. Oncotarget, 4 (11). ORCHARD PARK: IMPACT JOURNALS LLC. ISSN 1949-2553

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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. Pharmocologically inhibiting MYC expression may thus, have clinical utility given its pathogenic role in medulloblastoma. Recent studies using the selecting 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 pb3 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 medulloblastoma overexpressing MYC or harboring MYC amplifications.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Henssen, Anton UNSPECIFIED orcid.org/0000-0003-1534-778X UNSPECIFIED Thor, Theresa UNSPECIFIED UNSPECIFIED UNSPECIFIED Odersky, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Heukamp, Lukas UNSPECIFIED orcid.org/0000-0002-3388-3482 UNSPECIFIED El-Hindy, Nicolai UNSPECIFIED UNSPECIFIED UNSPECIFIED Beckers, Anneleen UNSPECIFIED UNSPECIFIED UNSPECIFIED Slpeleman, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Althoff, Kristina UNSPECIFIED UNSPECIFIED UNSPECIFIED Schaefers, Simon UNSPECIFIED UNSPECIFIED UNSPECIFIED Schramm, Alexander UNSPECIFIED orcid.org/0000-0001-7670-7529 UNSPECIFIED Sure, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Fleischhack, Gudrun UNSPECIFIED UNSPECIFIED UNSPECIFIED Eggert, Angelika UNSPECIFIED orcid.org/0000-0003-3476-8184 UNSPECIFIED Schulte, Johannes Hubertus UNSPECIFIED orcid.org/0000-0003-0671-1201 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-473630
DOI:	10.18632/oncotarget.1534
Journal or Publication Title:	Oncotarget
Volume:	4
Number:	11
Date:	2013
Publisher:	IMPACT JOURNALS LLC
Place of Publication:	ORCHARD PARK
ISSN:	1949-2553
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MYC; NEUROBLASTOMA; EXPRESSION; CHROMOSOMES; ACTIVATION; SUBGROUPS; RESPONSES; TUMOR Multiple languages Oncology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47363