Angiotensin System Inhibitors Are Associated with Improved Survival in Locally Advanced NSCLC and Exhibit Anti-Tumor Synergism with Chemotherapy in a Murine Model of NSCLC
Presented During:
Sunday, May 7, 2023: 7:30AM - 7:45AM
Los Angeles Convention Center
Posted Room Name:
408B
Abstract No:
102
Submission Type:
Abstract Submission
Authors:
Michael Lanuti (1), Hexiao Tang (2), Mozhdeh Sojoodi (1), Zenan Lin (3), Yongtao Wang (4), Derek Erstad (5), Eric Abston (1), Kenneth Tanabe (1), Hao Li (1), Michael Lanuti (1)
Institutions:
(1) Massachusetts General Hospital, Boston, MA, (2) Zhongnan Hospital of Wuhan University, Wu Han, China, (3) Guangdong Provincial People’s Hospital, Guangzhou, Guangdong, (4) Massachusetts General Hospital, Boston, MA, MA, (5) Baylor College of Medicine, Houston, TX
Submitting Author:
*Michael Lanuti
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Massachusetts General Hospital
Massachusetts General Hospital
Co-Author(s):
Hexiao Tang
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Zhongnan Hospital of Wuhan University
Zhongnan Hospital of Wuhan University
Mozhdeh Sojoodi
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Massachusetts General Hospital
Massachusetts General Hospital
Zenan Lin
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Guangdong Provincial People’s Hospital
Guangdong Provincial People’s Hospital
Yongtao Wang
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Massachusetts General Hospital
Massachusetts General Hospital
Derek Erstad
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Baylor College of Medicine
Baylor College of Medicine
Eric Abston
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Massachusetts General Hospital
Massachusetts General Hospital
Kenneth Tanabe
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Massachusetts General Hospital
Massachusetts General Hospital
Hao Li
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Massachusetts General Hospital
Massachusetts General Hospital
*Michael Lanuti
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Massachusetts General Hospital
Massachusetts General Hospital
Presenting Author:
*Michael Lanuti
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Massachusetts General Hospital
Massachusetts General Hospital
Abstract:
Objective: Several studies suggest that angiotensin system inhibitors can potentiate anti-tumor strategies in solid tumors. We investigated angiotensin system inhibitors (ASI) on outcomes in patients with locally advanced non-small cell lung cancer (NSCLC) and performed translational studies to elucidate anti-tumor mechanism in a murine model of NSCLC.
Methods: Survival outcomes of patients (N=125) diagnosed with clinical stage IIIA NSCLC treated with chemoradiotherapy followed by surgery (2009-2015) were correlated with ASI use in a single institutional cohort. To assess anti-tumor efficacy of ASI's, cell culture models of lung cancer were treated with Losartan or combination Losartan and Cisplatin in vitro and then applied to in vivo models. Mechanism was assessed with markers of endothelial-mesenchymal transition (EMT) or surrogates of other signalling pathways.
Results: In a cohort of 125 patents treated stage IIIA NSCLC, overall survival of ASI users (n=99) were compared to ASI non users (n=26). On multivariate analysis ASI use was independently associated with improved overall survival (p =0.047, HR 0.324). Further exploration at the bench with Losartan (≥0.5μM) significantly inhibited proliferation and migration of multiple human lung cancer cells in vitro including H441, H358, H1299, SW1573 and also in a syngeneic murine lung cancer cell line, TC-1. The combination of Losartan and Cisplatin significantly improved the cytotoxic effect of cisplatin (H441 p 0.043, H358 p 0.044, H1299 p 0.046, SW1573 p 0.020, TC-1 p 0.012) and significantly reduced the tumor volume of implanted subcutaneous tumors (SW1573-Nude mice, p=0.045; TC-1-C57BL/6 mice, p=0.001) in a murine flank model. Combination treatment significantly inhibited EMT and down-regulated the expression of AKT, Stat3, and PD-L1.
Conclusions: ASI use was associated with improved overall survival in a cohort of stage IIIA NSCLC . Losartan enhances the cytotoxic effect of chemotherapy in a dose dependent fashion in a murine model of NSCLC by attenuating the EMT pathway. This study suggests an important role for ASI therapy as an adjunct in the multi-modality cytotoxic treatment of lung cancer.
Methods: Survival outcomes of patients (N=125) diagnosed with clinical stage IIIA NSCLC treated with chemoradiotherapy followed by surgery (2009-2015) were correlated with ASI use in a single institutional cohort. To assess anti-tumor efficacy of ASI's, cell culture models of lung cancer were treated with Losartan or combination Losartan and Cisplatin in vitro and then applied to in vivo models. Mechanism was assessed with markers of endothelial-mesenchymal transition (EMT) or surrogates of other signalling pathways.
Results: In a cohort of 125 patents treated stage IIIA NSCLC, overall survival of ASI users (n=99) were compared to ASI non users (n=26). On multivariate analysis ASI use was independently associated with improved overall survival (p =0.047, HR 0.324). Further exploration at the bench with Losartan (≥0.5μM) significantly inhibited proliferation and migration of multiple human lung cancer cells in vitro including H441, H358, H1299, SW1573 and also in a syngeneic murine lung cancer cell line, TC-1. The combination of Losartan and Cisplatin significantly improved the cytotoxic effect of cisplatin (H441 p 0.043, H358 p 0.044, H1299 p 0.046, SW1573 p 0.020, TC-1 p 0.012) and significantly reduced the tumor volume of implanted subcutaneous tumors (SW1573-Nude mice, p=0.045; TC-1-C57BL/6 mice, p=0.001) in a murine flank model. Combination treatment significantly inhibited EMT and down-regulated the expression of AKT, Stat3, and PD-L1.
Conclusions: ASI use was associated with improved overall survival in a cohort of stage IIIA NSCLC . Losartan enhances the cytotoxic effect of chemotherapy in a dose dependent fashion in a murine model of NSCLC by attenuating the EMT pathway. This study suggests an important role for ASI therapy as an adjunct in the multi-modality cytotoxic treatment of lung cancer.
THORACIC:
Basic and Translational Research
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