Arylsulfonamide 64B Inhibits Hypoxia/HIF-Induced Expression of c-Met and CXCR4 and Reduces Primary Tumor Growth and Metastasis of Uveal Melanoma

• Type of Material: Article
• Authors: Lei Dong, Emory University; Shuo You, Emory University; Qing Zhang, Emory University; Saturo Osuka, Emory University; Narra S. Devi, Emory University; Stefan Kaluz, Emory University; Jalisa Nicole Holmes, Georgia State University; Hua Yang, Emory University; Guoliang Chen, Shenyang Pharmaceutical University; Binghe Wang, Emory University; Hans Grossniklaus, Emory University; Erwin Van Meir, Emory University
• Language: English
• Date: 2019-04-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 American Association for Cancer Research
• Final Published Version (URL): http://dx.doi.org/10.1158/1078-0432.CCR-18-1368
• Title of Journal or Parent Work: Clinical Cancer Research
• Volume: 25
• Issue: 7
• Start Page: 2206
• End Page: 2218
• Grant/Funding Information: This work was supported in part by the NIH (grants R01 CA116804, R01 CA176001, R01 CA180805, R24 EY017045, P30 EY06360 and P30 CA138292), a Fight For Sight Postdoctoral Award, the Emory Melanoma Prevention and Research Discovery Fund, a Winship Cancer Institute pilot grant, a Central South University Lieying pilot grant, the V Foundation, the Max Cure Foundation, the Samuel Waxman Cancer Research Foundation, the Alan B. Slifka Foundation, an unrestricted grant from Research to Prevent Blindness, Inc., and a grant from the National Natural Science Foundation of China (#81502544 to S.Y.).
• Keywords: Life Sciences & Biomedicine; Assay; Cells; Science & Technology; Oncology; Identification; Model; Cancer; Gene expression; Target; Activation
• Research Categories: Health Sciences, Opthamology; Health Sciences, Medicine and Surgery; Health Sciences, Oncology; Biology, Neuroscience

Abstract

Purpose: Uveal melanoma (UM) is the most prevalent and lethal intraocular malignancy in adults. Here, we examined the importance of hypoxia in UM growth and tested the antitumor effects of arylsulfonamide 64B, an inhibitor of the hypoxia-induced factor (HIF) pathway in animal models of UM and investigated the related mechanisms. Experimental Design: UM cells were implanted in the uvea of mice eyes and mice systemically treated with 64B. Drug effect on primary eye tumor growth, circulating tumor cells, metastasis formation in liver, and survival were examined. 64B effects on UM cell growth, invasion and hypoxia-induced expression of C-X-C chemokine receptor type 4 (CXCR4) and mesenchymal–epithelial transition factor (c-Met) were measured. Luciferase reporter assays, chromatin immunoprecipitation, co-immunoprecipitation, and cellular thermal shift assays were used to determine how 64B interferes with the HIF transcriptional complex. Results: Systemic administration of 64B had potent antitumor effects against UM in several orthotopic mouse models, suppressing UM growth in the eye (70% reduction) and spontaneous liver metastasis (50% reduction), and extending mice survival (P < 0.001) while being well tolerated. 64B inhibited hypoxia-induced expression of CXCR4 and c-Met, 2 key drivers of tumor invasion and metastasis. 64B disrupted the HIF-1 complex by interfering with HIF-1a binding to p300/CBP co-factors, thus reducing p300 recruitment to the MET and CXCR4 gene promoters. 64B could thermostabilize p300, supporting direct 64B binding to p300. Conclusions: Our preclinical efficacy studies support the further optimization of the 64B chemical scaffold toward a clinical candidate for the treatment of UM.