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Translational Therapeutics
British Journal of Cancer volume 131, pages 1683–1693 (2024)
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Ovarian cancer (OvCa) is the most lethal of the gynecologic malignancies. Immune checkpoint inhibitors, which have revolutionized the treatment of multiple malignancies, have had limited efficacy in OvCa patients. This lack of effectiveness is partly due to the abnormal ovarian tumor microenvironment (TME), displaying a desmoplastic, highly fibrotic extracellular matrix. High extracellular matrix deposition leads to a buildup of compressive forces that cause tumor blood vessel collapse, reduced vessel perfusion, poor delivery of drugs, and compromised trafficking of cytotoxic T-cells to these tumors.
Using two syngeneic OvCa models, we tested the effect of losartan, a widely prescribed anti-hypertensive drug, on reprogramming the TME and chemosensitizing the cancer cells.
Losartan treatment (i) reprograms the TME leading to increased vascular perfusion, and thus enhances drug delivery and immune effector cell intratumoral infiltration and function; and (ii) rewires the OvCa cells by suppressing the IGF-1 signaling, resulting in enhanced chemosensitivity. As a result of the combined tumor and stromal effects, losartan treatment enhances the efficacy of chemo-immunotherapy in OvCa models.
The safety and low cost ( < $1-2/day) of losartan warrant rapid translation of our findings to patients with OvCa.
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The data generated in this study are available upon request from the corresponding author.
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We thank Dr. Brian Seed for providing the cloning vector, we thank Mark Duquette, Naifang Lu, and Anna Khachatryan for their superb technical support, and Dr. Peigen Huang for assisting in animal studies.
This study was supported by the American Cancer Society Mission Boost Award (to L.X.), NIH R01-NS126187 and R01-DC020724 (to L.X.), Department of Defense Investigator-Initiated Research Award (W81XWH-20-1-0222, to L.X.) and Clinical Trial Award (W81XWH2210439, to L.X.), Children’s Tumor Foundation Drug Discovery Initiative (to L.X.); NIH grant R35-CA197743, and in part through grants R01- R01CA259253, R01-CA269672, R01-NS118929, U01-CA224348 and U01-CA261842 and by Nile Albright Research Foundation, the National Foundation for Cancer Research, Harvard Ludwig Cancer Center, and Jane’s Trust Foundation (to R.K.J.); and Nile Albright Research Foundation, Vincent Memorial Hospital Foundation, NCI P50CA240243, Julie Fund, Worden Family Foundation (to B.R.R).
Yao Sun & Zhiyong Yuan
Present address: Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Clinical Research for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
Yanxia Zhao
Present address: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430023, China
These authors contributed equally: Yao Sun, Zhenzhen Yin.
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
Yao Sun, Zhenzhen Yin, Shuang Li, Limeng Wu, Yanling Zhang, Yanxia Zhao, Igor L. Gomes dos Santos, Sonu Subudhi, Pinji Lei, Rakesh K. Jain & Lei Xu
Division of Biostatistics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
Alona Muzikansky
Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430023, China
Zhiyong Yuan
Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
Bo R. Rueda
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L.X. designed the research; Y.S., Z.Y., Y.Z. and S.L. performed mouse model studies; Y.S., L.W., S.L. performed histological studies; S.S. and P.L. analyzed RNASeq data; Y.S., L.W., B.R.R., and A.M. performed patient sample analysis; Y.S., Z.Y., L.W., Y.Z., I.L.G., S.S., P.L., A.M. and Z.Y. analyzed data; L.X. and R.K.J. wrote the paper.
Correspondence to Lei Xu.
R.K.J. received consultant fees from Cur, Elpis, Innocoll, SPARC, and SynDevRx; owns equity in Accurius, Enlight, and SynDevRx; is on the Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund; and received research grants from Boehringer Ingelheim and Sanofi. No funding or reagents from these companies were used in this study. B.R.R. reports serving on the advisory board for VincenTech which has no direct connection to the current research. The other authors have no competing interests to declare.
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Sun, Y., Yin, Z., Li, S. et al. Losartan rewires the tumor-immune microenvironment and suppresses IGF-1 to overcome resistance to chemo-immunotherapy in ovarian cancer. Br J Cancer 131, 1683–1693 (2024). https://doi.org/10.1038/s41416-024-02863-9
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DOI: https://doi.org/10.1038/s41416-024-02863-9
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