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BET bromodomain protein inhibition is a therapeutic option for medulloblastoma

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Item Type:Article
Title:BET bromodomain protein inhibition is a therapeutic option for medulloblastoma
Creators Name:Henssen, A. and Thor, T. and Odersky, A. and Heukamp, L. and El-Hindy, N. and Beckers, A. and Speleman, F. and Althoff, K. and Schäfers, S. and Schramm, A. and Sure, U. and Fleischhack, G. and Eggert, A. and Schulte, J.H.
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.
Keywords:BET Bromodomains, BRD4, MYC, JQ1, Pediatric Brain Tumors, Targeted Therapy, Animals, Mice
Publisher:Impact Journals
Page Range:2080-2095
Date:November 2013
Official Publication:https://doi.org/10.18632/oncotarget.1534
PubMed:View item in PubMed

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