The Bromodomain BET Inhibitor JQ1 Suppresses Tumor Angiogenesis in Models of Childhood Sarcoma

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...

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Published in:	Molecular cancer therapeutics Vol. 15; no. 5; pp. 1018 - 1028
Main Authors:	Bid, Hemant K, Phelps, Doris A, Xaio, Linlin, Guttridge, Denis C, Lin, Jiayuh, London, Cheryl, Baker, Laurence H, Mo, Xiaokui, Houghton, Peter J
Format:	Journal Article
Language:	English
Published:	United States 01-05-2016
Subjects:	Angiogenesis Inhibitors - pharmacology Animals Antineoplastic Agents - pharmacology Azepines - pharmacology Cell Line, Tumor Cell Movement - drug effects Cell Proliferation - drug effects Cell Survival - drug effects Child Disease Models, Animal Drug Resistance, Neoplasm - genetics Human Umbilical Vein Endothelial Cells Humans Mice Neovascularization, Pathologic - drug therapy Neovascularization, Pathologic - metabolism Proto-Oncogene Proteins c-myc - genetics Proto-Oncogene Proteins c-myc - metabolism Sarcoma - drug therapy Sarcoma - metabolism Sarcoma - pathology Transcription Factor AP-1 - metabolism Triazoles - pharmacology Xenograft Model Antitumor Assays
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current Address Doris A. Phelps, Greehey Children's Cancer Research Institute, UTHSCSA, 8403 Floyd Curl Drive, San Antonio, TX 78229-3000 Current Address Hemant Kumar Bid, PhD, Resonant Therapeutics, Inc., Life Sciences Institute, University of Michigan campus, Ann Arbor, MI.
ISSN:	1535-7163 1538-8514
DOI:	10.1158/1535-7163.mct-15-0567