Repurposing of a Thromboxane Receptor Inhibitor Based on a Novel Role in Metastasis Identified by Phenome-Wide Association Study.

Autor: Werfel TA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.; Department of Chemical Engineering, University of Mississippi, Oxford, Mississippi., Hicks DJ; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee., Rahman B; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee., Bendeman WE; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee., Duvernay MT; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee., Maeng JG; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee., Hamm H; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee., Lavieri RR; Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, Tennessee., Joly MM; Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, Tennessee., Pulley JM; Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, Tennessee., Elion DL; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee., Brantley-Sieders DM; Breast Cancer Research Program, Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee., Cook RS; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. rebecca.cook@vanderbilt.edu.; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.; Breast Cancer Research Program, Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.; Department of Biomedical Engineering, Vanderbilt University School of Engineering, Nashville, Tennessee.
Jazyk: angličtina
Zdroj: Molecular cancer therapeutics [Mol Cancer Ther] 2020 Dec; Vol. 19 (12), pp. 2454-2464. Date of Electronic Publication: 2020 Oct 08.
DOI: 10.1158/1535-7163.MCT-19-1106
Abstrakt: 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 A 2 -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.
(©2020 American Association for Cancer Research.)
Databáze: MEDLINE
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