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BET Bromodomain Inh...
BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma
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- 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
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- 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
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Nguyen, Brian (författare)
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Schubert, Simone (författare)
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Gholamin, Sharareh (författare)
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Tang, Yujie (författare)
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- Bolin, Sara (författare)
- Uppsala universitet,Cancer och vaskulärbiologi,Science for Life Laboratory, SciLifeLab,Swartling
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Schumacher, Steven E. (författare)
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Zeid, Rhamy (författare)
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Masoud, Sabran (författare)
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Yu, Furong (författare)
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Vue, Nujsaubnusi (författare)
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Gibson, William J. (författare)
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Paolella, Brenton R. (författare)
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Mitra, Siddhartha S. (författare)
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Cheshier, Samuel H. (författare)
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Qi, Jun (författare)
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Liu, Kun-Wei (författare)
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Wechsler-Reya, Robert (författare)
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- Weiss, William A. (författare)
- Department of Neurology, Pediatrics, and Neurosurgery, University of California, San Francisco, California
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- Swartling, Fredrik J., 1975- (författare)
- Uppsala universitet,Cancer och vaskulärbiologi,Science for Life Laboratory, SciLifeLab,Swartling
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Kieran, Mark W. (författare)
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- 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
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- 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;
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- 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.
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 20:4, s. 912-925
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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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
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- medulloblastoma
- MYC
- Oncology
- Onkologi
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Bandopadhayay, P ...
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Bergthold, Guill ...
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Nguyen, Brian
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Schubert, Simone
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Gholamin, Sharar ...
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Tang, Yujie
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visa fler...
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Bolin, Sara
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Schumacher, Stev ...
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Zeid, Rhamy
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Masoud, Sabran
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Yu, Furong
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Vue, Nujsaubnusi
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Gibson, William ...
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Paolella, Brento ...
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Mitra, Siddharth ...
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Cheshier, Samuel ...
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Qi, Jun
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Liu, Kun-Wei
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Wechsler-Reya, R ...
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Weiss, William A ...
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Swartling, Fredr ...
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Kieran, Mark W.
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Bradner, James E ...
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Beroukhim, Ramee ...
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Cho, Yoon-Jae
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