Naproxen Chemoprevention Promotes Immune Activation In Lynch Syndrome Colorectal Mucosa

Lynch syndrome (LS) patients are at markedly increased risk for colorectal cancer. It is being increasingly recognized that the immune system plays an essential role in LS tumor development. Therefore, immune interception strategies are emerging as a novel way to prevent cancer in LS. This phase Ib, placebo-controlled, randomized clinical trial and a co-clinical trial using a LS mouse model and patient-derived organoids aims to evaluate the safety and tolerability as well as to discover novel molecular pathways involved in the activity of Naproxen as chemoprevention in LS patients. Overall design: This is a phase Ib, placebo-controlled, randomized clinical trial of two doses (440mg and 220mg) of Naproxen administered daily over a period of 6 months from January 2014 to October 2017, and a co-clinical trial using a LS mouse model and patient-derived organoids to validate the biomarker results. There are 21 pre- and 21 paired post-treatment mRNAseq samples in human placebo group (PL), 14 pre- and 14 paired post-treatment mRNAseq samples in human low-dose (220mg) naproxen group (LD), 15 pre- and paired post-treatment mRNAseq samples in human high-dose (440mg) naproxen group (HD), 6 mRNAseq samples in patient-derived organoids control group and 6 paired mRNAseq samples in patient-derived organoids naproxen group, 3 independent mRNAseq samples in LS mouse model control group and 3 independent mRNAseq samples in LS mouse model naproxen group. All samples were sequenced by Illumina HiSeq4000 instrument that generated paired-end 75 or 76-base pair (bp) reads.