Proteomics techniques to find a possible predictor of response in a chemoprevention trial

Using new technology associated with the study of proteins, or proteomics, scientists at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), and their colleagues have made a step toward predicting which people with familial adenomatous polyposis (FAP), an inherited condition that often leads to colon cancer, will respond to the prevention drug celecoxib. This study, published in the April 15, 2004, issue of the journal Cancer Research, is the first to report using proteomics techniques to find a possible predictor of response in a chemoprevention trial.

Iqbal U. Ali, Ph.D., in the NCI Division of Cancer Prevention, and collaborators examined protein patterns among people who had been given celecoxib in a chemoprevention clinical trial in which the drug reduced the number of colon polyps characteristic of patients with FAP. Celecoxib inhibits an enzyme called cyclooxygenase 2, which has been associated with various cancers in addition to colon cancer. These clinical trial results were reported in June 2000 and led to approval by the Food and Drug Administration of celecoxib as a chemoprevention agent for people with FAP.

Not everyone in the 2000 study taking celecoxib experienced polyp reduction, however. Ali's group, employing a new proteomics technique, was able to distinguish the people who responded to the drug from those who did not.

Ali's laboratory used serum from the blood of 55 people who had participated in the celecoxib prevention trial. Serum contains tens of thousands of proteins. Using a specialized form of mass spectroscopy as a proteomics tool, the patients' proteins were separated and reported as a series of peaks. The pattern of protein peaks can be used to differentiate groups of patients.

The scientists analyzed blood obtained at the beginning of the prevention study--before participants received any celecoxib--and compared the pattern of protein peaks from the patients who didn't respond to the drug to the protein pattern of those who had a good response. One particular protein peak occurred in the serum of those people who did not benefit from the drug. The same protein peak was absent in those people whose polyps were reduced.

Although the technique has not been tested enough to be used in the clinic to identify those with FAP who will respond to celecoxib, the scientists are refining the technique for possible future clinical use.

"This study is a promising first step in using proteomics for personalized colon cancer prevention," said Ali. "A lot more work is needed before patients' responses to specific chemopreventive drugs can be reliably predicted."

In addition to predicting who responded to celecoxib, the scientists also used the proteomics technique to look at how protein patterns in each patient changed after being given the drug. They found that of thousands of possible proteins, only a few protein peaks were changed significantly in all patients following administration of celecoxib. The researchers are now trying to identify these proteins to learn more about how the drug works.

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