Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa

Laura Reyes-Uribe; Wenhui Wu; Ozkan Gelincik; Prashant V. Bommi; Alejandro Francisco-Cruz; Luisa M. Solis; Patrick M. Lynch; Ramona Lim; Elena M. Stoffel; Priyanka Kanth; N. Jewel Samadder; Maureen E. Mork; Melissa W. Taggart; Ginger L. Milne; Lawrence J. Marnett; Lana Vornik; Diane D. Liu; Maria Revuelta; Kyle Chang; Y. Nancy You; Levy Kopelovich; Ignacio I. Wistuba; J. Jack Lee; Shizuko Sei; Robert H. Shoemaker; Eva Szabo; Ellen Richmond; Asad Umar; Marjorie Perloff; Powel H. Brown; Steven M. Lipkin; Eduardo Vilar

doi:10.1136/gutjnl-2020-320946

Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa

Laura Reyes-Uribe, Wenhui Wu, Ozkan Gelincik, Prashant V. Bommi, Alejandro Francisco-Cruz, Luisa M. Solis, Patrick M. Lynch, Ramona Lim, Elena M. Stoffel, Priyanka Kanth, N. Jewel Samadder, Maureen E. Mork, Melissa W. Taggart, Ginger L. Milne, Lawrence J. Marnett, Lana Vornik, Diane D. Liu, Maria Revuelta, Kyle Chang, Y. Nancy YouLevy Kopelovich, Ignacio I. Wistuba, J. Jack Lee, Shizuko Sei, Robert H. Shoemaker, Eva Szabo, Ellen Richmond, Asad Umar, Marjorie Perloff, Powel H. Brown, Steven M. Lipkin, Eduardo Vilar

Gastroenterology and Hepatology

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English (US)
Pages (from-to)	555-566
Number of pages	12
Journal	Gut
Volume	70
Issue number	3
DOIs	https://doi.org/10.1136/gutjnl-2020-320946
State	Published - Mar 1 2021

Keywords

HNPCC syndrome
cancer syndromes
chemoprevention
gene expression
non-steroidal anti-inflammatory drugs

ASJC Scopus subject areas

Gastroenterology

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10.1136/gutjnl-2020-320946

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Reyes-Uribe, L., Wu, W., Gelincik, O., Bommi, P. V., Francisco-Cruz, A., Solis, L. M., Lynch, P. M., Lim, R., Stoffel, E. M., Kanth, P., Samadder, N. J., Mork, M. E., Taggart, M. W., Milne, G. L., Marnett, L. J., Vornik, L., Liu, D. D., Revuelta, M., Chang, K., ... Vilar, E. (2021). Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa. Gut, 70(3), 555-566. https://doi.org/10.1136/gutjnl-2020-320946

Reyes-Uribe, L, Wu, W, Gelincik, O, Bommi, PV, Francisco-Cruz, A, Solis, LM, Lynch, PM, Lim, R, Stoffel, EM, Kanth, P, Samadder, NJ, Mork, ME, Taggart, MW, Milne, GL, Marnett, LJ, Vornik, L, Liu, DD, Revuelta, M, Chang, K, You, YN, Kopelovich, L, Wistuba, II, Lee, JJ, Sei, S, Shoemaker, RH, Szabo, E, Richmond, E, Umar, A, Perloff, M, Brown, PH, Lipkin, SM & Vilar, E 2021, 'Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa', Gut, vol. 70, no. 3, pp. 555-566. https://doi.org/10.1136/gutjnl-2020-320946

@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.",

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 = "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",

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number = "3",

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TY - JOUR

T1 - Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa

AU - Reyes-Uribe, Laura

AU - Wu, Wenhui

AU - Gelincik, Ozkan

AU - Bommi, Prashant V.

AU - Francisco-Cruz, Alejandro

AU - Solis, Luisa M.

AU - Lynch, Patrick M.

AU - Lim, Ramona

AU - Stoffel, Elena M.

AU - Kanth, Priyanka

AU - Samadder, N. Jewel

AU - Mork, Maureen E.

AU - Taggart, Melissa W.

AU - Milne, Ginger L.

AU - Marnett, Lawrence J.

AU - Vornik, Lana

AU - Liu, Diane D.

AU - Revuelta, Maria

AU - Chang, Kyle

AU - You, Y. Nancy

AU - Kopelovich, Levy

AU - Wistuba, Ignacio I.

AU - Lee, J. Jack

AU - Sei, Shizuko

AU - Shoemaker, Robert H.

AU - Szabo, Eva

AU - Richmond, Ellen

AU - Umar, Asad

AU - Perloff, Marjorie

AU - Brown, Powel H.

AU - Lipkin, Steven M.

AU - Vilar, Eduardo

PY - 2021/3/1

Y1 - 2021/3/1

N2 - 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.

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.

KW - HNPCC syndrome

KW - cancer syndromes

KW - chemoprevention

KW - gene expression

KW - non-steroidal anti-inflammatory drugs

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UR - http://www.scopus.com/inward/citedby.url?scp=85100759135&partnerID=8YFLogxK

U2 - 10.1136/gutjnl-2020-320946

DO - 10.1136/gutjnl-2020-320946

M3 - Article

C2 - 32641470

AN - SCOPUS:85100759135

SN - 0017-5749

VL - 70

SP - 555

EP - 566

JO - Gut

JF - Gut

IS - 3

ER -

Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa

Abstract

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