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Repurposing of a Thromboxane Receptor Inhibitor Based on a Novel Role in Metastasis Identified by Phenome Wide Association Study Authors: Thomas A

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Repurposing of a Thromboxane Receptor Inhibitor Based on a Novel Role in Metastasis Identified by Phenome Wide Association Study Authors: Thomas A Author Manuscript Published OnlineFirst on October 8, 2020; DOI: 10.1158/1535-7163.MCT-19-1106 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Repurposing of a thromboxane receptor inhibitor based on a novel role in metastasis identified by Phenome Wide Association Study Authors: Thomas A. Werfel1, 7, Donna J. Hicks1, Bushra Rahman1, Wendy E. Bendeman1, Matthew T. Duvernay2, Jae G. Maeng2, Heidi Hamm2, Robert R. Lavieri3, Meghan M. Joly3, Jill M. Pulley3, David L. Elion4, Dana M. Brantley-Sieders5,6, Rebecca S. Cook1, 4, 5, 8* Affiliations: 1Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 USA 2Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232 USA 3Vanderbilt Institute for Clinical and Translational Research, Vanderbilt University Medical Center, Nashville, TN 37232 USA 4Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 USA 5Breast Cancer Research Program, Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232 USA 6Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232 7Department of Chemical Engineering, University of Mississippi, University, MS 38677 USA 8Department of Biomedical Engineering, Vanderbilt University School of Engineering, Nashville, TN 37232 USA *To whom correspondence should be addressed: Rebecca S. Cook, Ph.D. 759 Preston Research Building Vanderbilt University 2220 Pierce Avenue Nashville, TN 37232 Email: [email protected] Office phone: 615-936-3813 Conflict of Interest: CPI211 used in this study was provided by Cumberland Pharmaceuticals, Inc. (CPI). CPI had no role in study design, experimental conduct, data collection and analysis, or preparation of the manuscript. Additionally, CPI provided no direct financial support for this work. Compliance: BioVU data were utilized in accordance with all applicable institutional policies under IRB# 151121 Running title: Repurposing a TPr inhibitor to block cancer metastasis 1 Downloaded from mct.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 8, 2020; DOI: 10.1158/1535-7163.MCT-19-1106 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract: While 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 de-identified health records and matched genomic data from >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 a 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 trans-endothelial 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 anti-metastatic agents, and highlighting the use of PheWAS as an approach to accelerate drug repurposing. 2 Downloaded from mct.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 8, 2020; DOI: 10.1158/1535-7163.MCT-19-1106 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction The use of de-identified human genetic data tied to robust electronic health records (EHRs) enables discovery of human genotypes correlating with specific clinical conditions. This approach, known as phenome-wide association study (PheWAS), (1,2), can discover clinical ‘phenotypic’ indications associating with a genotypic variation, enabling discoveries of novel pathophysiological gene functions. From a translational perspective, PheWAS could predict potential opportunities for repurposing an existing catalog of molecularly targeted therapies (3), diminishing the risk, cost, and time needed for bringing treatments to patients. To test this principle, we used PheWAS to investigate repurposing opportunities for the drug CPI211 (4-6), a potent and highly selective small molecule inhibitor of thromboxane A2 and prostanoid receptor (TPr). CPI211 (PubChem ID 3037233) is safe and well tolerated, as shown in randomized, dose-escalating (≤1000 mg), placebo-controlled clinical trial (7). Decades of basic and translational science determined that TPr, expressed in platelets, endothelial cells (ECs), and smooth muscle cells, regulates different aspects of cardiovascular homeostasis. TPr dysregulation contributes to venous hypertension, pulmonary hypertension, thrombosis and asthma, steering development of CPI211 and other TPr antagonists toward these clinical indications (8,9). However, aberrant activation of TPr may have yet undiscovered pathological consequences for which TPr inhibitors might be effective. Since pathologically increased TPr expression can be caused by naturally occurring single nucleotide polymorphisms (SNPs) within the TPr gene, TBXA2R, w 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). Several previously described SNPs within TBXA2R are known to alter TPr expression, some that diminish TPr and thus correlate with decreased platelet function (11), and others that 3 Downloaded from mct.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 8, 2020; DOI: 10.1158/1535-7163.MCT-19-1106 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. increase TPr expression. As might be expected, the SNPs that increase TPr expression are known to correlate with advanced cardiovascular disease (12-14) or asthma (15). We investigated one TBXA2R SNP that increases TPr expression, rs200445019. This SNP was selected based on its occurrence within the TBXA2R coding region, generating a threonine-to- alanine alteration at residue 399 (T399A) within the C-terminus of the TPr splice variant, TPr-β (https://www.ncbi.nlm.nih.gov/snp/rs200445019/), the domain of TPr-β driving TPr desensitization, internalization, trafficking, and proteosomal degradation (16-19). Following ligand activation, TPr signaling activates protein kinase C (PKC), a serine threonine kinase which then phosphorylates TPr-β T399, inducing TPr internalization and degradation. TPr T399 mutation causes loss of PKC-mediated TPr phosphorylation, and loss of ligand-induced receptor downregulation. Thus, the TPr-β T399A substitution generated by rs200445019 results in greater TPr expression and signaling, supporting use of rs200445019 as a genomic proxy for increased TPr in PheWAS analyses. Here, we report that PheWAS analysis of rs200445019 identified a novel and unexpected correlation between rs200445019 and metastatic cancer diagnoses, and that the TPr inhibitor CPI211 blocked metastasis in multiple cancer models. Materials and Methods The BioVU biorepository at Vanderbilt University Medical Center (VUMC) contains >250,000 de- identified DNA samples extracted from excess patient blood samples collected during routine clinical testing, linked to corresponding, longitudinal clinical and demographic data derived from Synthetic Derivative, a de-identified electronic health record (EHR) built for research purposes (20,21). BioVU data were utilized in accordance with VUMC IRB# 151121. The allelic variant of focus was the TBXA2R missense SNP rs200445019, selected based on the presence of meaningful validation signals in the PheWAS results to support inference of variant effects in vivo, including hypertension and cardiovascular indications, phenotypes expected to be observed if TPr function was enhanced. 4 Downloaded from mct.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 8, 2020; DOI: 10.1158/1535-7163.MCT-19-1106 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. PheWAS using previously reported methods (22) focused on 29,722 patients of European ancestry genotyped using the Illumina
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