Skip to main content

BET bromodomain inhibition of MYC-amplified medulloblastoma.

Publication ,  Journal Article
Bandopadhayay, P; Bergthold, G; Nguyen, B; Schubert, S; Gholamin, S; Tang, Y; Bolin, S; Schumacher, SE; Zeid, R; Masoud, S; Yu, F; Vue, N ...
Published in: Clinical cancer research : an official journal of the American Association for Cancer Research
February 2014

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.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.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.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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Clinical cancer research : an official journal of the American Association for Cancer Research

DOI

EISSN

1557-3265

ISSN

1078-0432

Publication Date

February 2014

Volume

20

Issue

4

Start / End Page

912 / 925

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Triazoles
  • Transcription Factors
  • Signal Transduction
  • Proto-Oncogene Proteins c-myc
  • Oncology & Carcinogenesis
  • Nuclear Proteins
  • Mice, SCID
  • Mice, Inbred NOD
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Bandopadhayay, P., Bergthold, G., Nguyen, B., Schubert, S., Gholamin, S., Tang, Y., … Cho, Y.-J. (2014). BET bromodomain inhibition of MYC-amplified medulloblastoma. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 20(4), 912–925. https://doi.org/10.1158/1078-0432.ccr-13-2281
Bandopadhayay, Pratiti, Guillaume Bergthold, Brian Nguyen, Simone Schubert, Sharareh Gholamin, Yujie Tang, Sara Bolin, et al. “BET bromodomain inhibition of MYC-amplified medulloblastoma.Clinical Cancer Research : An Official Journal of the American Association for Cancer Research 20, no. 4 (February 2014): 912–25. https://doi.org/10.1158/1078-0432.ccr-13-2281.
Bandopadhayay P, Bergthold G, Nguyen B, Schubert S, Gholamin S, Tang Y, et al. BET bromodomain inhibition of MYC-amplified medulloblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2014 Feb;20(4):912–25.
Bandopadhayay, Pratiti, et al. “BET bromodomain inhibition of MYC-amplified medulloblastoma.Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, vol. 20, no. 4, Feb. 2014, pp. 912–25. Epmc, doi:10.1158/1078-0432.ccr-13-2281.
Bandopadhayay P, Bergthold G, Nguyen B, Schubert S, Gholamin S, Tang Y, Bolin S, Schumacher SE, Zeid R, Masoud S, Yu F, Vue N, Gibson WJ, Paolella BR, Mitra SS, Cheshier SH, Qi J, Liu K-W, Wechsler-Reya R, Weiss WA, Swartling FJ, Kieran MW, Bradner JE, Beroukhim R, Cho Y-J. BET bromodomain inhibition of MYC-amplified medulloblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2014 Feb;20(4):912–925.

Published In

Clinical cancer research : an official journal of the American Association for Cancer Research

DOI

EISSN

1557-3265

ISSN

1078-0432

Publication Date

February 2014

Volume

20

Issue

4

Start / End Page

912 / 925

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Triazoles
  • Transcription Factors
  • Signal Transduction
  • Proto-Oncogene Proteins c-myc
  • Oncology & Carcinogenesis
  • Nuclear Proteins
  • Mice, SCID
  • Mice, Inbred NOD
  • Mice