@article{b7a19406797b4de79e0eaa89393b0903,
title = "Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa",
abstract = "Objective Patients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS. Design We conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs). Results Overall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control. Conclusions Naproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity. Trial registration number gov Identifier: NCT02052908 ",
keywords = "HNPCC syndrome, cancer syndromes, chemoprevention, gene expression, non-steroidal anti-inflammatory drugs",
author = "Laura Reyes-Uribe and Wenhui Wu and Ozkan Gelincik and Bommi, {Prashant V.} and Alejandro Francisco-Cruz and Solis, {Luisa M.} and Lynch, {Patrick M.} and Ramona Lim and Stoffel, {Elena M.} and Priyanka Kanth and Samadder, {N. Jewel} and Mork, {Maureen E.} and Taggart, {Melissa W.} and Milne, {Ginger L.} and Marnett, {Lawrence J.} and Lana Vornik and Liu, {Diane D.} and Maria Revuelta and Kyle Chang and You, {Y. Nancy} and Levy Kopelovich and Wistuba, {Ignacio I.} and Lee, {J. Jack} and Shizuko Sei and Shoemaker, {Robert H.} and Eva Szabo and Ellen Richmond and Asad Umar and Marjorie Perloff and Brown, {Powel H.} and Lipkin, {Steven M.} and Eduardo Vilar",
note = "Funding Information: Twitter Prashant V Bommi @koolmolecule, Alejandro Francisco-Cruz @inhoutes, Maria Revuelta @vic_rev and Eduardo Vilar @evilarsan Acknowledgements We thank the patients and their families for their participation. We thank the clinical coordinators from all the study sites (Valerie O Sepeda, Chinedu I Ukaegbu, Michelle Westover, Erika Koeppe) and the UTMDACC Clinical Cancer Prevention Research Core for their assistance in the conduction of this study. This project was supported in part by the Translational Molecular Pathology-Immunoprofiling lab at the UTMDACC Department Translational Molecular Pathology (Wei Lu, Lakshmi Kakarala, Mei Jiang, Jianling Zhou, Ou Shi and Jocelyn Coronel). We thank the staff of the Microarray and Sequencing Core Facility at UTMDACC and Weill Cornell Medical College for the assistance with RNA sequencing. The authors are grateful to Charles M Bowen for critically reading the manuscript and the anonymous reviewers for their helpful comments that improved the manuscript. Funding Information: Funding This work was supported by grants R01 CA219463 and contract HHSN261201200034I (US National Institutes of Health/National Cancer Institute), and a gift from the Feinberg Family to EV; a grant from the Emerson Cancer Collective Research Foundation (ECCRF 192069), and contract HHSN261201500039I (US National Institutes of Health/National Cancer Institute) to SL; and P30 CA016672 (US National Institutes of Health/National Cancer Institute) to the University of Texas MD Anderson Cancer Center Core Support Grant. Publisher Copyright: {\textcopyright} ",
year = "2021",
month = mar,
day = "1",
doi = "10.1136/gutjnl-2020-320946",
language = "English (US)",
volume = "70",
pages = "555--566",
journal = "Gut",
issn = "0017-5749",
publisher = "BMJ Publishing Group",
number = "3",
}