Although new drug discoveries are revolutionizing cancer treatments, repurposing existing drugs would accelerate the timeline and lower the cost for bringing treatments to cancer patients. Our goal was to repurpose CPI211, a potent and selective antagonist of the thromboxane A2-prostanoid receptor (TPr), a G-protein–coupled receptor that regulates coagulation, blood pressure, and cardiovascular homeostasis. To identify potential new clinical indications for CPI211, we performed a phenome-wide association study (PheWAS) of the gene encoding TPr, TBXA2R, using robust deidentified health records and matched genomic data from more than 29,000 patients. Specifically, PheWAS was used to identify clinical manifestations correlating with a TBXA2R single-nucleotide polymorphism (rs200445019), which generates a T399A substitution within TPr that enhances TPr signaling. Previous studies have correlated 200445019 with chronic venous hypertension, which was recapitulated by this PheWAS analysis. Unexpectedly, PheWAS uncovered an rs200445019 correlation with cancer metastasis across several cancer types. When tested in several mouse models of metastasis, TPr inhibition using CPI211 potently blocked spontaneous metastasis from primary tumors, without affecting tumor cell proliferation, motility, or tumor growth. Further, metastasis following intravenous tumor cell delivery was blocked in mice treated with CPI211. Interestingly, TPr signaling in vascular endothelial cells induced VE-cadherin internalization, diminished endothelial barrier function, and enhanced transendothelial migration by tumor cells, phenotypes that were decreased by CPI211. These studies provide evidence that TPr signaling promotes cancer metastasis, supporting the study of TPr inhibitors as antimetastatic agents and highlighting the use of PheWAS as an approach to accelerate drug repurposing.

中文翻译：

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基于 Phenome Wide Association 研究确定的转移中新作用的血栓素受体抑制剂的再利用

尽管新药的发现正在彻底改变癌症治疗，但重新利用现有药物将加快时间并降低为癌症患者提供治疗的成本。我们的目标是重新利用 CPI211，一种有效的选择性血栓素 A2-前列腺素受体 (TPr) 拮抗剂，TPr 是一种调节凝血、血压和心血管稳态的 G 蛋白偶联受体。为了确定 CPI211 的潜在新临床适应症，我们使用来自超过 29,000 名患者的可靠的去识别健康记录和匹配的基因组数据，对编码 TPr 的基因 TBXA2R 进行了全表型关联研究 (PheWAS)。具体来说，PheWAS 用于识别与 TBXA2R 单核苷酸多态性（rs200445019）相关的临床表现，它在 TPr 内产生 T399A 替代，增强 TPr 信号传导。以前的研究已将 200445019 与慢性静脉性高血压相关联，这一 PheWAS 分析概括了这一点。出乎意料的是，PheWAS 发现 rs200445019 与几种癌症类型的癌症转移相关。在几种小鼠转移模型中进行测试时，使用 CPI211 抑制 TPr 可有效阻断原发性肿瘤的自发转移，而不影响肿瘤细胞增殖、运动或肿瘤生长。此外，在用 CPI211 治疗的小鼠中，静脉内肿瘤细胞递送后的转移被阻断。有趣的是，血管内皮细胞中的 TPr 信号传导诱导 VE-钙粘蛋白内化，降低内皮屏障功能，增强肿瘤细胞的跨内皮迁移，CPI211 降低的表型。这些研究提供了 TPr 信号促进癌症转移的证据，支持了 TPr 抑制剂作为抗转移剂的研究，并强调了使用 PheWAS 作为加速药物再利用的方法。