Abstract 25: Targeting c-Myc in pediatric sarcoma xenografts with the BET bromodomain inhibitor, JQ1, disrupts angiogenesis

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 19_Supplement; p. 25
• Main Authors: Bid, Hemant Kumar, Phelps, Doris A., Xiao, Linlin, Baker, Laurence, Qi, Jun, Houghton, Peter J.
• Format: Journal Article
• Language: English
• Published: 01-10-2014
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2014-25

Abstract
Histone acetylation regulates activation and repression of multiple angiogenesis and inflammatory genes known to play critical roles in the pathogenesis of various diseases. The current study was designed to elucidate the therapeutic potential of JQ1, an inhibitor of the BET class of human bromodomain proteins (“readers” of histone acetylation marks), in pediatric sarcomas. Surprisingly, our results demonstrated that in-vivo xenografts showed similar sensitivity to JQ1, despite their cell lines showing >20 fold differences in sensitivity in-vitro. cMYC expression significantly down regulated in most rhabdomyosarcoma cell lines after JQ1 treatment, however there was no significant down regulation of cMYC in Ewings sarcoma lines, despite similar sensitivities to JQ1. When administered to mice bearing human sarcoma xenografts, JQ1 (50mg/kg/d) significantly retarded tumor growth. Whereas Ki67 staining remained unchanged in treated tumors, CD34-positive staining decreased after 2 weeks of treatment. Microvessel density (CD34-positive cells) in tumors of JQ1-treated animals was reduced by at least 60% compared with controls (P < 0.01) indicating anti-angiogenic activity. Assay of angiogenic factors in JQ1 treated tumor xenografts showed that 7 factors were significantly downregulated compared to control tumors in all four sarcoma lines. To test the anti-angiogenic activity of JQ1 directly we exposed primary cultured human umbilical vascular endothelial cells (HUVEC) to JQ1 (500 nM). JQ1 significantly inhibited vascular endothelial growth factor (VEGF) induced proliferation, migration, invasion, adhesion and capillary-like structure formation by HUVECs in a concentration-dependent manner. Furthermore, JQ1 (50 mg/kg/d) abrogated VEGF-induced vascular formation and reduced hemoglobin levels in the mouse Matrigel plug assay in vivo. To understand the molecular mechanism of these activities, we next examined the signaling pathways in HUVECs treated with JQ1 using a proteome based angiogenesis array as well as transcription factor activation assay. JQ1 treatment considerably decreased various angiogenic factors as well as dramatically decreasing AP1 expression and it transcriptional activity. This study provides evidence that JQ1 induces a wide range of effects on endothelial cells that lead to inhibition of tumor angiogenesis and demonstrate that the role of BRD4 inhibitors as a therapeutic strategy to target vasculature. Supported by a grant from SARC.
Citation Format: Hemant Kumar Bid, Doris A. Phelps, Linlin Xiao, Laurence Baker, Jun Qi, Peter J. Houghton. Targeting c-Myc in pediatric sarcoma xenografts with the BET bromodomain inhibitor, JQ1, disrupts angiogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 25. doi:10.1158/1538-7445.AM2014-25