title: The Bromodomain BET Inhibitor JQ1 Suppresses Tumor Angiogenesis in Models of Childhood Sarcoma.
abstract: The bromodomain and extra-terminal domain inhibitor JQ1 has marked antitumor activity against several hematologic malignancies as well as solid tumor models. Here, we investigated its activity in vitro and in vivo against models of childhood rhabdomyosarcoma and Ewing sarcoma. In vitro, JQ1 (but not the inactive enantiomer JQ1R) inhibited cell proliferation and increased G1 fraction of cells, although there was no correlation between cell line sensitivity and suppression of c-MYC or MYCN. In vivo, xenografts showed significant inhibition of growth during the period of treatment, and rapid regrowth after treatment was stopped, activity typical of antiangiogenic agents. Furthermore, xenografts derived from cell lines intrinsically resistant or sensitive to JQ1 in vitro had similar sensitivity in vivo as xenografts. Further investigation showed that JQ1 reduced tumor vascularization. This was secondary to both drug-induced downregulation of tumor-derived growth factors and direct effects of JQ1 on vascular elements. JQ1 suppressed VEGF-stimulated vascularization of Matrigel plugs in mice, and in vitro suppressed differentiation, proliferation, and invasion of human umbilical cord vascular endothelial cells (HUVEC). In HUVECs, JQ1 partially suppressed c-MYC levels, but dramatically reduced AP-1 levels and activity through suppression of the AP-1-associated protein FOSL1. Our data suggest that the antitumor activity of JQ1 in these sarcoma models is largely a consequence of its antiangiogenic activity. Mol Cancer Ther; 15(5); 1018-28. ©2016 AACR.
authors.affiliation: Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Bid
authors.affiliation: Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Doris A
authors.initials: DA
authors.lastname: Phelps
authors.affiliation: Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Linlin
authors.initials: L
authors.lastname: Xaio
authors.affiliation: Center for Regenerative Medicine, Ohio State University, Columbus, Ohio.
authors.forename: Denis C
authors.initials: DC
authors.lastname: Guttridge
authors.affiliation: Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Jiayuh
authors.initials: J
authors.lastname: Lin
authors.affiliation: College of Veterinary Medicine, Ohio State University, Columbus, Ohio.
authors.forename: Cheryl
authors.initials: C
authors.lastname: London
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Baker
authors.affiliation: Center for Biostatistics, Ohio State University, Columbus, Ohio.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.affiliation: Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio. Greehey Children's Cancer Research Institute, San Antonio, Texas. houghtonp@uthscsa.edu.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C561695:(+)-JQ1 compound; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D001381:Azepines; D016271:Proto-Oncogene Proteins c-myc; D018808:Transcription Factor AP-1; D014230:Triazoles