Targeting C-Myc In Pediatric Sarcoma Xenografts With The Bet Bromodomain Inhibitor, Jq1, Disrupts Angiogenesis

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 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