Study shows naproxen promotes immune activation in Lynch syndrome patients
A Phase I chemoprevention clinical trial led by MD Anderson researchers found that naproxen, an over-the-counter anti-inflammatory drug, is safe to take daily and activates immune pathways in the colorectal mucosa of people living with Lynch syndrome.
The results were published July 8 in Gut and presented at the AACR Virtual Annual Meeting I (Poster CT111). Lynch syndrome is an inherited condition that increases a person’s chances of developing certain cancers, particularly colorectal cancer. Chemopreventive strategies could be particularly beneficial for people with Lynch syndrome because they have about a 70% lifetime risk of colorectal cancer.
Study shows naxproxen is safe, activates immune pathways
In previous pre-clinical research, the team, led by Eduardo Vilar-Sanchez, M.D., Ph.D., associate professor of Clinical Cancer Prevention, found that naproxen effectively prevented colorectal cancer in Lynch syndrome mouse models.
In the new multicenter Phase I clinical trial, investigators randomized 80 participants with Lynch syndrome to receive high-dose naproxen (440 mg), low-dose naproxen (220 mg) or a placebo by mouth daily for six months. Participants were evenly split across the trial arms, with 25 people in the high-dose group, 27 in the low-dose group and 28 in the placebo group. Toxicity was assessed throughout the study. No severe adverse events related to treatment were reported, and the total number of minor adverse events was similar across all treatment arms. “Our study showed that taking naproxen chronically is a very safe intervention,” says Laura Reyes, M.D., postdoctoral fellow in Clinical Cancer Prevention. “We also learned that naproxen not only reduces prostaglandin levels, but also activated specific immune pathways.”
Prostaglandin E2 (PGE2) is an inflammatory marker that’s associated with colorectal cancer. Researchers took blood and urine samples before and after the intervention and, as expected, found PGE2 levels were significantly lower in both groups treated with the anti-inflammatory drug, compared to the placebo.
Participants underwent colonoscopies at the beginning and end of the six-month intervention. Researchers used next-generation sequencing (mRNAseq) to study how the intervention affected gene expression in the colon tissue. In the high-dose naproxen group, researchers found enriched immune-related pathways, suggesting a local activation of immune cells within the colorectal mucosa.
“The traditional view of naproxen is that it’s a mechanism to reduce inflammation,” Vilar-Sanchez says. “We’ve shown it goes beyond that to actually stimulate immune cells in the colorectal mucosa. Naproxen activates T cells and dendritic cells to kill pre-malignant cells hidden in the colorectal mucosa.”
Findings could provide insight for colorectal cancer vaccine development
“Immune cell enrichment analysis revealed gene expression profiles that could serve as predictive biomarkers of chemopreventive drug activity,” Reyes says. “This is relevant because our next step is to develop colorectal cancer vaccines for people with Lynch syndrome, and we're looking for compounds that are safe and help in immune activation.”
Ultimately, the research team aims to combine naproxen chemoprevention with the development of a vaccine to effectively prevent colorectal cancer by activating the immune system in the high-risk Lynch Syndrome population.