Dataset Information

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.

SUBMITTER: Reyes-Uribe L

PROVIDER: S-EPMC7790993 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa.

Reyes-Uribe Laura L Wu Wenhui W Gelincik Ozkan O Bommi Prashant V PV Francisco-Cruz Alejandro A Solis Luisa M LM Lynch Patrick M PM Lim Ramona R Stoffel Elena M EM Kanth Priyanka P Samadder N Jewel NJ Mork Maureen E ME Taggart Melissa W MW Milne Ginger L GL Marnett Lawrence J LJ Vornik Lana L Liu Diane D DD Revuelta Maria M Chang Kyle K You Y Nancy YN Kopelovich Levy L Wistuba Ignacio I II Lee J Jack JJ Sei Shizuko S Shoemaker Robert H RH Szabo Eva E Richmond Ellen E Umar Asad A Perloff Marjorie M Brown Powel H PH Lipkin Steven M SM Vilar Eduardo E

Gut 20200708 3

<h4>Objective</h4>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.<h4>Design</h4>We conducted a Phase ...[more]

PMID: 32641470

Similar Datasets

Project description:BackgroundInternational chemoprevention preferences and approaches in Lynch syndrome (LS) and APC-associated polyposis, including Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP) have not been previously explored.AimTo describe current chemoprevention strategies for patients with LS or FAP/AFAP (referred to collectively as FAP) practiced by members of four international hereditary cancer societies through administration of a survey.ResultsNinety-six participants across four hereditary gastrointestinal cancer societies responded to the survey. Most respondents (91%, 87/96) completed information regarding their demographics and practice characteristics relating to hereditary gastrointestinal cancer and chemoprevention clinical practices. Sixty-nine percent (60/87) of respondents offer chemoprevention for FAP and/or LS as a part of their practice. Of the 75% (72/96) of survey respondents who were eligible to answer practice-based clinical vignettes based off of their responses to ten barrier questions regarding chemoprevention, 88% (63/72) of those participants completed at least one case vignette question to further characterize chemoprevention practices in FAP and/or LS. In FAP, 51% (32/63) would offer chemoprevention for rectal polyposis, with sulindac - 300 mg (18%, 10/56) and aspirin (16%, 9/56) being the most frequently selected options. In LS, 93% (55/59) of professionals discuss chemoprevention and 59% (35/59) frequently recommend chemoprevention. Close to half of the respondents (47%, 26/55) would recommend beginning aspirin at time of commencement of the patient's first screening colonoscopy (usually at age 25yrs). Ninety-four percent (47/50) of respondents would consider a patient's diagnosis of LS as an influential factor for aspirin use. There was no consensus on the dose of aspirin (≤100 mg, >100 mg - 325 mg or 600 mg) to offer patients with LS and there was no agreement on how other factors, such as BMI, hypertension, family history of colorectal cancer, and family history of heart disease, would affect the recommendation for aspirin use. Possible harm among older patients (>70 years) was identified as the most common reason to discourage aspirin use.ConclusionAlthough chemoprevention is widely discussed and offered to patients with FAP and LS by an international group of hereditary gastrointestinal cancer experts, there is significant heterogeneity in how it is applied in clinical practice.

Dataset Information

Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa.

Objective

Design

Results

Conclusions

Trial registration number

Publications

Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa.

Similar Datasets

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