People with Lynch syndrome face a high risk of colorectal cancer. But researchers think that reducing this risk may be as easy as taking a daily over-the-counter pill.
Chemoprevention in Lynch syndrome
Up to 5% of colorectal cancers are caused by Lynch syndrome, which results from germline mutations in the DNA mismatch repair genes. Lynch syndrome increases the risk of colorectal cancer from around 5% to 50%-80%. Researchers have found that chemoprevention with daily high-dose aspirin can reduce the cancer risks associated with Lynch syndrome. However, the potential for gastrointestinal bleeding or other problems from the long-term use of high-dose aspirin may discourage physicians from prescribing this treatment.
A possible alternative to high-dose aspirin for chemoprevention was found when a mouse model of Lynch syndrome showed that naproxen was a more effective chemoprotective agent than aspirin. This chemoprotective effect was seen even at relatively low doses of naproxen. On the basis of these results, the National Cancer Institute approached Eduardo Vilar Sanchez, M.D., Ph.D., an assistant professor in the Department of Clinical Cancer Prevention at MD Anderson Cancer Center, to arrange a phase I placebo-controlled double-blind trial of naproxen in participants with Lynch syndrome. He and his colleagues are studying the safety of naproxen in this group as well as the molecular changes that the drug induces in the normal colorectal mucosa.
In the ongoing trial, study participants receive a daily dose of placebo or 440 mg or 220 mg of naproxen. Both naproxen dosages are similar to the over-the-counter recommended dose (one or two 220-mg tablets).
Study participants undergo a colonoscopy at baseline and after 6 months of treatment. Researchers measure prostaglandin E2 levels and other proteins in participants’ blood, urine, and tissue samples to determine how long-term use of naproxen affects tissues, messenger RNA, and microRNA signatures. The tissue samples are also analyzed for biomarkers that may help determine who will benefit most from naproxen chemoprevention. The researchers are also studying possible side effects such as ulcers, heart attacks, and kidney problems.
The trial has recruited about 30 patients from MD Anderson and other centers. So far, naproxen has been well tolerated, and preliminary safety results were reported in July at the European Society for Medical Oncology’s World Congress on Gastrointestinal Cancer. Because the trial is double-blind, efficacy results will not be available until after the trial has been completed.
“At the conference, we also demonstrated the feasibility of recruiting healthy participants with rare genetic mutations into clinical trials,” Vilar Sanchez said. “In the past, it has been challenging to execute and complete clinical trials for carriers of rare mutations.”
The trial is still accruing patients, with a goal of 60 participants. The phase I trial will end in December 2016, and Vilar Sanchez plans to launch a phase II clinical trial in 2017 to investigate whether naproxen at safe doses can prevent cancer.
This article originally appeared in the October 2015 issue of OncoLog.