Unlocking the mechanisms underlying aspirin’s effects on cancer
By Andy Koopmans
Could something as simple as aspirin be a major weapon against cancer? Dr. Brian Reid and his colleagues in the Human Biology and Public Health Sciences divisions at Fred Hutchinson Cancer Research Center researchers have been awarded almost $1.9 million over the next four years from the National Cancer Institute’s Provocative Questions Project to find out.
The project grew out of a series of workshops led by NCI director Dr. Harold Varmus to define new directions for cancer research in the United States, with the goal of ultimately funding more challenging and creative research and urging researchers to tackle the perplexing questions of cancer research.
Reid’s group will tackle one of 20 perplexing questions
The group of cancer research veterans assembled came up with 20 such perplexing questions, and Reid’s group will be looking into one interrogating the mechanism underlying the link between cancer and aspirin and other non-steroidal anti-inflammatory drugs: “What is the molecular mechanism by which a drug (such as aspirin or metformin) that is chronically used for other indications protects against cancer incidence and mortality?”
“The mechanism is an empty box right now. Our job is to start filling it in,” Reid said, adding that the link is tantalizing. In very large randomized trials where patients were given aspirin or other NSAIDs to prevent cardiovascular disease, follow-up data show that those patients died less frequently of numerous cancers: esophageal, gastric, colon, lung and others. “If we know what the mechanism is, we could design drugs to combat cancer that do what aspirin and NSAIDs do, except without the side effects, the major one of which is bleeding from the GI tract,” Reid said.
Aspirin and other NSAIDs associated with decreased risk of esophageal cancer
Reid’s group has been studying Barrett’s esophagus, a disorder in which the lining of the esophagus is damaged by stomach acid and is also a known risk factor for esophageal cancer. Reid’s group is basing their research on preliminary studies they’ve conducted with the Seattle Barrett’s Esophagus Cohort, a dynamic patient cohort started at University of Washington in 1983 that includes more than 900 participants. Their preliminary studies with these patients have shown that aspirin and NSAIDs decrease certain types of chromosome mutations that give rise to esophageal adenocarcinoma.
One study showed that participants who have used aspirin and other NSAIDs had a much lower incidence of going on to develop cancer and a lower incidence of chromosomal abnormalities. Another showed that people who already had the chromosomal abnormalities still had their risk drop significantly if they took aspirin: over a period of 10 years, 30 percent of those who took aspirin or other NSAIDs developed cancer compared to 80 percent of those who did not.
As part of their grant research, Reid’s group intends to collect biopsy samples and DNA from the cohort and sequence their genes, then match against sequencing data for 150 esophageal cancers released this year by the Cancer Genome Atlas.
Reid foresees two possible outcomes to the research: one is that they’ll find that aspirin and NSAIDs work on certain kinds of mutations. If they can then uncover the mechanism behind how that happens, that could lead to a personalized-medicine approach in which people with those particular mutations can be prescribed drugs that act on the underlying genetic abnormality.
But according to Reid, the second possibility is even more exciting. “What if we find out that aspirin is decreasing all mutations? If we could find the mechanism behind that, then that would be huge. If it turns out that all of a sudden we have a way to control the fundamental thing that causes cancer, then we could potentially eliminate or dramatically decrease mutations and enormously lower cancer mortality across the population.”
A team effort
Reid said that he is excited by the challenge of the work ahead, acknowledging that no research, particularly of this scope, can happen without a strong, efficient team. His Fred Hutch colleagues include researchers Xiaohong Li, Tom Vaughan, Patty Galipeau, Rissa Sanchez, Patricia Blount, Tom Paulson, Dave Cowan, Christine Karlsen and Amber Karnofski
“And the patients, of course. They’ve all been wonderful,” he said.
This is the second year that Fred Hutch scientists have participated in the Provocative Questions Project. In 2012, NCI awarded more than $22 million to 57 grants recipients nationwide, including three Fred Hutch scientists: Drs. Denise Galloway, Patrick Paddison, and Robert Eisenman, who are all entering the second year of their research on their questions. Their projects look into the link between novel infectious agents and cancers, why certain mutational events promote cancer phenotypes in some tissues and not others and new technologies to inhibit traditionally undruggable target molecules required for cancer growth.