BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma

被引：277

作者：

Bandopadhayay, Pratiti ^{[1
,3
,4
,6
]}

Bergthold, Guillaume ^{[1
,6
]}

Nguyen, Brian ^{[7
]}

Schubert, Simone ^{[7
]}

Gholamin, Sharareh ^{[8
]}

Tang, Yujie ^{[7
]}

Bolin, Sara ^{[12
]}

Schumacher, Steven E. ^{[1
,6
]}

Zeid, Rhamy ^{[2
]}

Masoud, Sabran ^{[7
]}

Yu, Furong ^{[7
]}

Vue, Nujsaubnusi ^{[7
]}

Gibson, William J. ^{[1
,6
]}

Paolella, Brenton R. ^{[1
,6
]}

Mitra, Siddhartha S. ^{[8
]}

Cheshier, Samuel H. ^{[8
]}

Qi, Jun ^{[2
]}

Liu, Kun-Wei ^{[10
]}

Wechsler-Reya, Robert ^{[10
]}

Weiss, William A. ^{[11
]}

Swartling, Fredrik J. ^{[12
]}

Kieran, Mark W. ^{[3
,4
]}

Bradner, James E. ^{[2
,6
]}

Beroukhim, Rameen ^{[1
,2
,5
,6
]}

Cho, Yoon-Jae ^{[7
,8
,9
]}

机构：

[1] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[4] Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA USA

[5] Dana Farber Canc Inst, Ctr Canc Genome Characterizat, Boston, MA 02115 USA

[6] Broad Inst MIT & Harvard, Cambridge, MA USA

[7] Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA

[8] Stanford Univ, Sch Med, Dept Neurosurg, Stanford, CA 94305 USA

[9] Stanford Univ, Med Ctr, Stanford Canc Inst, Stanford, CA 94305 USA

[10] Sanford Burnham Med Res Inst, NCI Designated Canc Ctr, Tumor Initiat & Maintenance Program, La Jolla, CA USA

[11] Univ Calif San Francisco, Dept Neurol Pediat & Neurosurg, San Francisco, CA 94143 USA

[12] Uppsala Univ, Rudbeck Lab, Sci Life Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden

来源：

CLINICAL CANCER RESEARCH | 2014年 / 20卷 / 04期

基金：

瑞典研究理事会;

关键词：

CIRCULAR BINARY SEGMENTATION; ADJUVANT CHEMOTHERAPY; HISTONE H3.3; BRAIN-TUMORS; N-MYC; SUBGROUPS; PROLIFERATION; CHILDHOOD; SURVIVAL; THERAPY;

D O I：

10.1158/1078-0432.CCR-13-2281

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma. Experimental Design: We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC orMYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice. Results: Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G(1) and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index. Conclusion: JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma. (C)2013 AACR.

引用

页码：912 / 925

页数：14

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