Abstract
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.
Highlights
The use of deidentified human genetic data tied to robust electronic health records (EHR) enables discovery of human genotypes correlating with specific clinical conditions
Because pathologically increased thromboxane A2 and prostanoid receptor (TPr) expression can be caused by naturally occurring single-nucleotide polymorphisms (SNP) within the TPr gene, TBXA2R, we propose that phenome-wide association study (PheWAS) analysis using these previously identified and characterized TBXA2R SNPs as a genomic proxy for increased TPr expression could identify clinical manifestations correlating with increased TPr expression [10]
We identified a novel and unexpected correlation between TPr and tumor metastasis using a combination of PheWAS analyses in large population data sets, gene-expression studies in clinical cancer data sets, and pharmacologic blockade of TPr activity in models of metastasis (Supplementary Fig. S3)
Summary
The use of deidentified human genetic data tied to robust electronic health records (EHR) enables discovery of human genotypes correlating with specific clinical conditions. This approach, known as phenome-wide association study 1, 2), can discover clinical “phenotypic” indications associating with a genotypic variation, enabling discoveries of novel pathophysiologic gene functions. To test this principle, we used PheWAS to investigate repurposing opportunities for the drug CPI211 [4,5,6], a potent and highly selective small-molecule inhibitor of thromboxane A2 and prostanoid receptor (TPr). Because pathologically increased TPr expression can be caused by naturally occurring single-nucleotide polymorphisms (SNP) within the TPr gene, TBXA2R, we propose that PheWAS analysis using these previously identified and characterized TBXA2R SNPs as a genomic proxy for increased TPr expression could identify clinical manifestations correlating with increased TPr expression [10]
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