

Could Blocking Inflammation
Stop Cancer from Forming?

The Holy Grail, for scientists studying evolution, is the idea of a "missing link," a creature somewhere between man and ape, to explain how humans came to be. Scientists studying prostate cancer are also looking for missing links-more than one, certainly-to explain the complicated journey through which a normal cell evolves into a cancerous one. What lies between Point A and Point B?

One step before prostate cancer is PIN, prostatic intraepithelial neoplasia, or "funny-looking" cells that aren't normal, but aren't quite cancerous. One likely step before that, as pathologist Angelo De Marzo, M.D. , Ph.D., discovered a couple of years ago, is PIA, proliferative inflammatory atrophy-cells that appear to be shut down, or atrophied, and are surrounded with inflammation. PIA cells, despite their appearance, are actually volatile, with wildly fluctuating levels of glutathione-S -transferase p, which protects against prostate cancer. Is early inflammation of the prostate an important step-even a missing link- to cancer? And is this inflammation a "done deal," or is it reversible?

Oncologists Michael A. Carducci, M.D. , and Theodore DeWeese, M.D. , of the Brady Urological Institute and the Kimmel Cancer Center, interested in the idea of reversing the steps leading to cancer through "chemoprevention," are hoping to find out.

They have started a clinical trial, funded by the National Cancer Institute, of antiinflammatory drugs called COX (cyclooxygenase) inhibitors-a class of drugs that includes NSAIDS (nonsteroidal antiinflammatory drugs) and even plain old aspirin. The particular drug in this trial, a selective COX-2 inhibitor (which has fewer side effects than aspirin and other drugs in this class) called celecoxib, was developed as a treatment for arthritis. "But it turns out," says Carducci, "that the COX-2 inhibitors also interact heavily with the pathways that are important for cancer progression. The idea, bolstered by research from Angelo De Marzo, Bill Nelson, Ted DeWeese, and others, is that early inflammatory injury-and whether or not the body's able to repair it-may be the next step to forming cancer. And new evidence suggests that when there's inflammation, growth factors are produced that promote blood vessel growth, and this also may increase the likelihood that cancer will develop. So it's becoming increasingly clear that maybe just blocking this pathway could delay disease. "

COX inhibitors are known to lower someone's risk of developing colon cancer; they also may help prevent esophageal cancer, and some recent studies suggest that men who regularly take aspirin and other COX inhibitors are less likely to develop prostate cancer.

"Our research (done in collaboration with Brady molecular geneticist Bill Isaacs) suggests that if these inhibitors do work, they don't seem to be working by directly affecting the cancer cells themselves," says De Marzo, "because the target protein of the inhibitor is not present in prostate cancer cells. It's only present in some of the inflammatory cells, the white blood cells, and in the PIA cells themselves. So it suggests that if these drugs really do inhibit prostate cancer-if these are little fires burning in the prostate-this might put them out." These early cells, De Marzo notes, are a different kettle of fish altogether from advanced cancer cells.

"We want to see whether this is something we should be giving very early in the disease, to someone who's at high risk, or if taking this could help prevent prostate cancer, like an aspirin a day for your heart. "


"When we examine a prostate that's been removed for cancer-even in the ones where there is not a lot of cancer- we see several little, separate cancers," says De Marzo. "If we could decrease the rate of formation of these little cancers-prevent new lesions from forming-we might stop the big cancers. "

In Carducci's new study, which is "double- blind"-meaning the doctors don't know who is getting the drug, and who is getting a placebo-men who are scheduled to undergo radical prostatectomy will be given celecoxib for about six weeks, from the time their cancer is diagnosed until the time of surgery. De Marzo, explaining the need to make the study "blind," quotes Brady scientist Don Coffey, Ph.D. "As Dr. Coffey says, you don't see with your eyes, you see with your mind, what you expect to see. If you can't possibly see it, that's the only way to make it really valid. "

"The idea," says Carducci, "is to look a short-term exposure, and see what the effect of the drug is on inflammation, angiogenesis (growth of new blood vessels to feed the cancer), DNA damage, and cell proliferation. " After the men undergo surgery, De Marzo will examine the removed prostate tissue.

If the COX inhibitor shows promise, the study will be expanded. "We want to see whether this is something we should be giving very early in the disease, to someone who's at high risk, or if taking this could help prevent prostate cancer, like an aspirin a day for your heart," says Carducci.

De Marzo is conducting longer-term laboratory studies to see whether giving COX inhibitors can prevent prostate cancer in rats. "It would be nice one day," he envisions, "to give this to younger men, in their 30s and 40s, and say, you don't have cancer yet, but you have a high risk. Start taking these fairly nontoxic drugs, and they may prevent your prostate cancer, and incidentally, prevent colon cancer. We're not there yet, but that's the real potential payoff. "



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