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Raymond N. DuBois, M.D., Ph.D. and colleagues at the Vanderbilt-Ingram Cancer Center partnered with pharmaceutical and biotech firms to publish several papers in 2003 that have illuminated the pathways stimulated by cyclooxygenase-2 (COX-2).
DuBois, a long-time NCI grantee, was the first to report the role of the enzyme COX-2 in colon cancer. Since then, several COX-2 inhibitors, which suppress inflammation in the body, have been suggested as anti-cancer agents. One,
celecoxib, was recently approved as an adjunct to traditional preventive measures in a group of patients genetically predisposed to colorectal cancer.
"It's looking more and more like mediators involved with chronic inflammation, such as COX-2 and prostaglandins, stimulate progression to cancer," says DuBois. "If we can target those, we should be able to inhibit progression of the tumor."
One study demonstrated a new pathway COX-2 uses to stimulate growth, migration, and invasiveness of colorectal cancer cells. The researchers found that prostaglandin E2, a product of COX-2 activity, triggers the epidermal growth
factor receptor (EGFR), an important signaling molecule involved in the aggressive growth and spread of a variety of cancers. Several EGFR inhibitors exist, and DuBois says that early studies suggest that blocking both EGFR and COX-2 might have an additive effect.
In a second study, the team paired a COX-2 inhibitor with a matrix metalloproteinase (MMP) inhibitor in mice that are susceptible to colon cancer. The two drugs work on separate signaling pathways, and they did a better job in combination than either drug alone in reducing the number of adenomas in the mice. Importantly, the scientists were able to give the drugs at doses low enough to avoid side effects. The scientists wrote,"These compounds together could represent an easily tolerated chemopreventive regimen."
In a third study, the researchers explored how another signaling receptor, PPAR-gamma, blocks cancer cell growth and induces cell differentiation - two key steps
in preventing cancer formation. This study opens the door to a potential new class of cancer prevention agents that activate PPAR-gamma specifically in epithelial
cells in the colon.
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