title: BET bromodomain inhibition of MYC-amplified medulloblastoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Authors' Affiliations: Departments of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School; Pediatric Neuro-Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Pediatric Hematology/Oncology, Boston Children's Hospital; Center for Cancer Genome Characterization, Dana-Farber Cancer Institute, Boston; The Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Departments of Neurology and Neurological Sciences and Neurosurgery, Stanford University School of Medicine; Stanford Cancer Institute, Stanford University Medical Center, Stanford; Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla; Department of Neurology, Pediatrics, and Neurosurgery, University of California, San Francisco, California; and Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Pratiti
authors.initials: P
authors.lastname: Bandopadhayay
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bergthold
authors.forename: Brian
authors.initials: B
authors.lastname: Nguyen
authors.forename: Simone
authors.initials: S
authors.lastname: Schubert
authors.forename: Sharareh
authors.initials: S
authors.lastname: Gholamin
authors.forename: Yujie
authors.initials: Y
authors.lastname: Tang
authors.forename: Sara
authors.initials: S
authors.lastname: Bolin
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schumacher
authors.forename: Rhamy
authors.initials: R
authors.lastname: Zeid
authors.forename: Sabran
authors.initials: S
authors.lastname: Masoud
authors.forename: Furong
authors.initials: F
authors.lastname: Yu
authors.forename: Nujsaubnusi
authors.initials: N
authors.lastname: Vue
authors.forename: William J
authors.initials: WJ
authors.lastname: Gibson
authors.forename: Brenton R
authors.initials: BR
authors.lastname: Paolella
authors.forename: Siddhartha S
authors.initials: SS
authors.lastname: Mitra
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Cheshier
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.forename: Kun-Wei
authors.initials: KW
authors.lastname: Liu
authors.forename: Robert
authors.initials: R
authors.lastname: Wechsler-Reya
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.forename: Fredrik J
authors.initials: FJ
authors.lastname: Swartling
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002470:Cell Survival; D059585:G1 Phase Cell Cycle Checkpoints; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C489427:MYC protein, human