PT  - JOURNAL ARTICLE
AU  - Laura Reyes-Uribe
AU  - Wenhui Wu
AU  - Ozkan Gelincik
AU  - Prashant V Bommi
AU  - Alejandro Francisco-Cruz
AU  - Luisa M Solis
AU  - Patrick M Lynch
AU  - Ramona Lim
AU  - Elena M Stoffel
AU  - Priyanka Kanth
AU  - N Jewel Samadder
AU  - Maureen E Mork
AU  - Melissa W Taggart
AU  - Ginger L Milne
AU  - Lawrence J Marnett
AU  - Lana Vornik
AU  - Diane D Liu
AU  - Maria Revuelta
AU  - Kyle Chang
AU  - Y Nancy You
AU  - Levy Kopelovich
AU  - Ignacio I Wistuba
AU  - J Jack Lee
AU  - Shizuko Sei
AU  - Robert H Shoemaker
AU  - Eva Szabo
AU  - Ellen Richmond
AU  - Asad Umar
AU  - Marjorie Perloff
AU  - Powel H Brown
AU  - Steven M Lipkin
AU  - Eduardo Vilar
TI  - Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa
AID  - 10.1136/gutjnl-2020-320946
DP  - 2021 Mar 01
TA  - Gut
PG  - 555--566
VI  - 70
IP  - 3
4099  - http://gut.bmj.com/content/70/3/555.short
4100  - http://gut.bmj.com/content/70/3/555.full
SO  - Gut2021 Mar 01; 70
AB  - 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