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Sökning: onr:"swepub:oai:DiVA.org:uu-217950" > BET Bromodomain Inh...

BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma

Bandopadhayay, Pratiti (författare)
Departments of Cancer Biology and Pediatric Neuro-Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Pediatric Hematology/Oncology, Boston Children's Hospital; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
Bergthold, Guillaume (författare)
Departments of Cancer Biology, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Pediatric Hematology/Oncology, Boston Children's Hospital; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
Nguyen, Brian (författare)
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Schubert, Simone (författare)
Gholamin, Sharareh (författare)
Tang, Yujie (författare)
Bolin, Sara (författare)
Uppsala universitet,Cancer och vaskulärbiologi,Science for Life Laboratory, SciLifeLab,Swartling
Schumacher, Steven E. (författare)
Zeid, Rhamy (författare)
Masoud, Sabran (författare)
Yu, Furong (författare)
Vue, Nujsaubnusi (författare)
Gibson, William J. (författare)
Paolella, Brenton R. (författare)
Mitra, Siddhartha S. (författare)
Cheshier, Samuel H. (författare)
Qi, Jun (författare)
Liu, Kun-Wei (författare)
Wechsler-Reya, Robert (författare)
Weiss, William A. (författare)
Department of Neurology, Pediatrics, and Neurosurgery, University of California, San Francisco, California
Swartling, Fredrik J., 1975- (författare)
Uppsala universitet,Cancer och vaskulärbiologi,Science for Life Laboratory, SciLifeLab,Swartling
Kieran, Mark W. (författare)
Bradner, James E. (författare)
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
Beroukhim, Rameen (författare)
Departments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School; Center for Cancer Genome Characterization, Dana-Farber Cancer Institute, Boston; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts;
Cho, Yoon-Jae (författare)
Departments of Neurology and Neurological Sciences and Neurosurgery, Stanford University School of Medicine; Stanford Cancer Institute, Stanford University Medical Center, Stanford
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 (creator_code:org_t)
2014
2014
Engelska.
Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 20:4, s. 912-925
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • 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 or MYCN. 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 G1 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.

Ämnesord

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine (hsv//eng)

Nyckelord

medulloblastoma
MYC
Oncology
Onkologi

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