P04.5. Repurposing Cholesterol-Lowering Statins to Overcome Esophageal Cancer Therapy Resistance, From Bench to Bedside

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ID: 325962
2026
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Ranked #52 of 453 articles by views in diseases of the esophagus : official journal of the international society for diseases of the esophagus

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Abstract
Abstract Topic Esophageal Cancer: Adjuvant and Neo-Adjuvant Therapies Background Esophageal cancer is the seventh cause of cancer mortality worldwide. Despite recent advances in the perioperative management of esophageal adenocarcinoma with systemic and immunotherapy, significant therapy resistance persists. New approaches are in demand, and repurposing approved drugs for other indications is an attractive and low-cost approach to address this issue. Interfering with the adaptive metabolism of cancer cells holds promise, but complexity and redundancy makes it challenging to identify specific targets. Lipid and cholesterol metabolism play a key role in cancer cell homeostasis. Statins are ubiquitous cholesterol-lowering oral agents that could have a role in esophageal malignancy. Methods With a focus on esophageal adenocarcinoma (EAC), inputs from our single center highly annotated clinical database and biobank comprising more than 400 esophageal cancer patients were integrated. We used single-cell RNA sequencing data from a select cohort and employed an artificial intelligence-driven platform called NeMoCAD (Network Model for Causality-Aware Discovery) to predict compounds capable of reversing cancer cells transcriptomic state. High-throughput drug screening and synergy assays were employed to assess the in vitro effect of statins alone or in combination with chemotherapy on a patient-derived organoid cancer model. Parallel to this, we collected retrospective data from our prospectively maintained clinical database for analysis of demographics, tumor characteristics, response to systemic therapy and survival, grouping patients by statin use status. Results: With the NeMoCAD algorithm several statins were predicted to potentially alter the transcriptomic profile of chemoresistant tumours to resemble that of normal surrounding tissues, notably simvastatin and atorvastatin. Drg screening and synergy assays showed statins alone displayed variable cytotoxicity and that overall interaction patterns with chemotherapy were additive, but yielding peak synergy scores at low concentrations. From our clinical database, 449 locally advanced EAC patients receiving curative-intent neoadjuvant chemotherapy followed by surgery were included. A quarter of patients were on cholesterol-lowering statins for cardiovascular indications (n=128). They were significantly older and had higher BMI. A 30% increase in major pathological response was seen in statin users (NS) as well as significantly improved overall survival (5-year OS 54.1% vs 40.7%, HR 0.69, p=0.019). This impact was more pronounced for those receiving current standard-of-care FLOT. Of note, lipophilic statins (e.g., Atorvastatin, Simvastatin) showed better survival outcomes than hydrophilic statins. Conclusion In EAC, statins may play a role in improving response to neo-adjuvant systemic chemotherapy and may lead to prolonged survival in this population. Our clinical observations are in accordance, with increased overall survival (HR 0.69) for statin users. Moreover, these observations validate the predictions of in silico models employed, further corroborated by in vitro synergy essays. Confirmation of these findings is planned within a phase 2 clinical trial.
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Authors Luís Castro, Sanjima Pal, Megan Sperry, Yi Yan, Shuyuan Wang, Mingyang Kong, Ruo Yu Ma, Qian Qiu, Nicholas Bertos, Mehrnoush Dehghani, Andrew Meng, Carmen Mueller, J. Cools-Lartigue, Mathieu Rousseau, Sara Najmeh, Jonathan Spicer, Donald Ingber, Lorenzo Ferri
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Journal diseases of the esophagus : official journal of the international society for diseases of the esophagus
Year 2026
DOI
10.1093/dote/doag077.003
URL
https://academic.oup.com/dote/article-pdf/39/Supplement_1/doag077.003/70760390/doag077.003.pdf
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