Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma

Yanxia Zhao, Jinghong Cao, Alexander Melamed, Michael Worley, Allison Gockley, Dennis Jones, Hadi T. Nia, Yanling Zhang, Triantafyllos Stylianopoulos, Ashwin S. Kumar, Fotios Mpekris, Meenal Datta, Yao Sun, Limeng Wu, Xing Gao, Oladapo Yeku, Marcela G. del Carmen, David R. Spriggs, Rakesh K. Jain, and Lei Xu
PNAS February 5, 2019 116 (6) 2210-2219; published ahead of print February 5, 2019 https://doi.org/10.1073/pnas.1818357116

  1. Contributed by Rakesh K. Jain, December 7, 2018 (sent for review October 26, 2018; reviewed by John Hays and Fan Yuan)

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Significance

Despite initial responsiveness to chemotherapy, the overwhelming majority of advanced ovarian cancer patients relapse with resistant disease. Thus, developing more effective strategies for ovarian cancer treatment is a high clinical priority. Here, we report that targeting angiotensin signaling with losartan, an angiotensin receptor blocker, can reduce extracellular matrix in ovarian tumors and the associated physical barriers that normally hinder drug delivery and efficacy. These changes in the tumor microenvironment lead to improved response to chemotherapy, and, importantly, decrease ascites—a major burden for ovarian cancer patients. These preclinical findings are in concert with our retrospective analysis showing improved survival in patients receiving angiotensin system inhibitors concurrently with standard treatment for ovarian cancer and should be tested in a clinical trial.

Abstract

In ovarian cancer patients, tumor fibrosis and angiotensin-driven fibrogenic signaling have been shown to inversely correlate with survival. We sought to enhance drug delivery and therapeutic efficacy by remodeling the dense extracellular matrix in two orthotopic human ovarian carcinoma xenograft models. We hypothesized that targeting the angiotensin signaling axis with losartan, an approved angiotensin system inhibitor, could reduce extracellular matrix content and the associated “solid stress,” leading to better anticancer therapeutic effect. We report here four translatable findings: (i) losartan treatment enhances the efficacy of paclitaxel—a drug used for ovarian cancer treatment—via normalizing the tumor microenvironment, resulting in improved vessel perfusion and drug delivery; (ii) losartan depletes matrix via inducing antifibrotic miRNAs that should be tested as candidate biomarkers of response or resistance to chemotherapy; (iii) although losartan therapy alone does not reduce tumor burden, it reduces both the incidence and the amount of ascites formed; and (iv) our retrospective analysis revealed that patients receiving angiotensin system inhibitors concurrently with standard treatment for ovarian cancer exhibited 30 mo longer overall survival compared with patients on other antihypertensives. Our findings provide the rationale and supporting data for a clinical trial on combined losartan and chemotherapy in ovarian cancer patients.

Footnotes

  • ↵1Present address: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430023 Hubei, China.

  • ↵2Present address: Department of Obstetrics and Gynecology, Beijing TongRen Hospital, Capital Medical University, 100730 Beijing, China.

  • ↵3Present address: Department of Oral and Maxillofacial Surgery, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, China.

  • ↵4To whom correspondence may be addressed. Email: jain{at}steele.mgh.harvard.edu or lei{at}steele.mgh.harvard.edu.

  • Author contributions: Y. Zhao, J.C., D.J., H.T.N., T.S., O.Y., D.R.S., R.K.J., and L.X. designed research; Y. Zhao, J.C., A.M., M.W., A.G., D.J., H.T.N., Y. Zhang, T.S., A.S.K., F.M., M.D., Y.S., L.W., X.G., O.Y., M.G.d.C., and L.X. performed research; Y. Zhao, J.C., A.M., M.W., A.G., D.J., H.T.N., Y. Zhang, T.S., A.S.K., F.M., M.D., Y.S., L.W., X.G., O.Y., M.G.d.C., D.R.S., R.K.J., and L.X. analyzed data; and Y. Zhao, J.C., A.M., M.W., D.J., H.T.N., T.S., M.D., O.Y., D.R.S., R.K.J., and L.X. wrote the paper.

  • Reviewers: J.H., The Ohio State University Wexner Medical Center; and F.Y., Duke University.

  • Conflict of interest statement: R.K.J. received an honorarium from Amgen; consultant fees from Merck, Ophthotech, Pfizer, SPARC, SynDevRx, and XTuit; owns equity in Enlight, Ophthotech, and SynDevRx; and serves on the boards of trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund. Neither any reagent nor any funding from these organizations was used in this study.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1818357116/-/DCSupplemental.

Published under the PNAS license.

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Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma
Yanxia Zhao, Jinghong Cao, Alexander Melamed, Michael Worley, Allison Gockley, Dennis Jones, Hadi T. Nia, Yanling Zhang, Triantafyllos Stylianopoulos, Ashwin S. Kumar, Fotios Mpekris, Meenal Datta, Yao Sun, Limeng Wu, Xing Gao, Oladapo Yeku, Marcela G. del Carmen, David R. Spriggs, Rakesh K. Jain, Lei Xu
Proceedings of the National Academy of Sciences Feb 2019, 116 (6) 2210-2219; DOI: 10.1073/pnas.1818357116
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