癌症研究
肾透明细胞癌
转录因子
癌症
HIF1A型
缺氧诱导因子
生物
细胞周期蛋白D1
肾细胞癌
血管生成
医学
细胞周期
内科学
基因
生物化学
作者
Eli M. Wallace,James P. Rizzi,Guangzhou Han,Paul M. Wehn,Zhaodan Cao,Xinlin Du,Tzuling Cheng,Robert Czerwiński,Darryl D. Dixon,Barry S. Goggin,Jonas Grina,Megan M. Halfmann,Melissa A. Maddie,Sarah R. Olive,Stephen T. Schlachter,Huiling Tan,Bin Wang,Keshi Wang,Shanhai Xie,Rui Xu
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2016-09-07
卷期号:76 (18): 5491-5500
被引量:276
标识
DOI:10.1158/0008-5472.can-16-0473
摘要
Abstract More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel–Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2α that allosterically blocks its dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1β. PT2385 inhibited the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. Treatment of tumor-bearing mice with PT2385 caused dramatic tumor regressions, validating HIF2α as a pivotal oncogenic driver in ccRCC. Notably, unlike other anticancer agents that inhibit VEGF receptor signaling, PT2385 exhibited no adverse effect on cardiovascular performance. Thus, PT2385 represents a novel class of therapeutics for the treatment of RCC with potent preclincal efficacy as well as improved tolerability relative to current agents that target the VEGF pathway. Cancer Res; 76(18); 5491–500. ©2016 AACR.
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