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Original research
Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa
  1. Laura Reyes-Uribe1,
  2. Wenhui Wu1,
  3. Ozkan Gelincik2,
  4. Prashant V Bommi1,
  5. Alejandro Francisco-Cruz3,
  6. Luisa M Solis3,
  7. Patrick M Lynch4,5,
  8. Ramona Lim6,
  9. Elena M Stoffel7,
  10. Priyanka Kanth8,
  11. N Jewel Samadder9,
  12. Maureen E Mork5,
  13. Melissa W Taggart10,
  14. Ginger L Milne11,
  15. Lawrence J Marnett11,
  16. Lana Vornik1,
  17. Diane D Liu12,
  18. Maria Revuelta2,
  19. Kyle Chang1,
  20. Y Nancy You5,13,
  21. Levy Kopelovich2,
  22. Ignacio I Wistuba3,
  23. J Jack Lee12,
  24. Shizuko Sei14,
  25. Robert H Shoemaker14,
  26. Eva Szabo14,
  27. Ellen Richmond14,
  28. Asad Umar14,
  29. Marjorie Perloff14,
  30. Powel H Brown1,
  31. Steven M Lipkin2,
  32. Eduardo Vilar1,5
  1. 1 Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  2. 2 Weill Cornell Medical College, New York, New York, USA
  3. 3 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  4. 4 Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  5. 5 Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  6. 6 Department of Gastroenterology, Dana Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts, USA
  7. 7 Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
  8. 8 Division of Gastroenterology, Department of Medicine, University of Utah/Huntsman Cancer Institute, Salt Lake City, Utah, USA
  9. 9 Department of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, Arizona, USA
  10. 10 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  11. 11 Departments of Biochemistry, Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  12. 12 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  13. 13 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  14. 14 Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland, USA
  1. Correspondence to Dr Eduardo Vilar, Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; evilar{at}mdanderson.org

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

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

  • Twitter @koolmolecule, @inhoutes, @vic_rev, @evilarsan

  • SML and EV contributed equally.

  • Contributors SL and EV had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. YNY, LV, LK, SS, RS, ES, AU, PM, PB, SL and EV helped in the study concept and design. Identification of study subjects and provision of clinical information was performed by PML, YNY, ES, RL, PK, JS, and EV. ES, ER, AU, PM, LV, PB and EV provided supervision to the clinical study. LRU, OG, PB, GM and LM processed and prepared case samples for analysis, sequencing and mass spectrometry analysis. AFC, LS, MWT and IW helped in pathology interpretation and histomorphometry analysis. WW, KC, MR, DL, JJL, SL and EV analysed sequencing data and performed statistical analysis. LRU, WW, KC, PB, MR, OG, SL and EV analysed and discussed the data. LRU, WW, PB, OG, AFC, SL and EV helped in writing of the manuscript. All authors edited and approved the content of this manuscript.

  • 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.

  • Competing interests JS has a consulting role with Janssen Research and Development, and Cancer Prevention Pharmaceuticals. IW has an advisory role with Genentech/Roche, Bayer, Bristol-Myers Squibb, AstraZeneca/Medimmune, Pfizer, HTG Molecular, Asuragen, Merck, GlaxoSmithKline, Guardant Health and MSD, has received speaker fees from Medscape, MSD, Genentech/Roche, Pfizer and received research support from Genentech, Oncoplex, HTG Molecular, DepArray, Merck, Bristol-Myers Squibb, Medimmune, Adaptive, Adaptimmune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, Iovance, 4D, Novartis, and Akoya. SL and EV are co-principal investigators in an NIH/NCI U01 award with co-investigators employed by Nouscom, s.r.l. EV has a consulting and advisory role with Janssen Research and Development and Recursion Pharma.

  • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting or dissemination plans of this research. Refer to the Methods section for further details.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available in a public, open access repository. RNA-seq files have been deposited in GEO. The following links can be used to access the data for reanalysis: GSE144381 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE144381

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