Looking for Markers

Besides being the Brady's new research director, Robert Getzenberg, Ph.D., professor of urology, is searching for better, smarter tests and biomarkers for prostate cancer and other diseases.


Is it cancer, or another prostate problem? One of his first targets is PSA. A major drawback to using PSA (prostate-specific antigen) to detect cancer is that it doesn't show only cancer, Getzenberg says. "PSA is a normal product of the prostate that is found at high levels even within the normal prostate." Men who have a PSA of between 4 and 10 ng/mlhave roughly a 25 percent chance of having prostate cancer, he continues, "which means that more than 75 percent of the men biopsied do not have the disease."

So Getzenberg has been wondering: What does prostate cancer make, that normal prostate tissue doesn't? And he's found what may be a good answer: "We have developed a novel biomarker for prostate cancer called early prostate cancer antigen (EPCA)," he says."One interesting characteristic is that this marker is elevated not only in the prostate cancer itself, but in the entire prostate of men with the disease." However, he adds, men who don'thave prostate cancer - even men with other prostate problems, such as BPH and prostatitis- don't show any EPCA within their prostate.

EPCA, which is already available as a test for pathologists to use, could be particularly useful in evaluating negative prostate biopsies: If a stain of prostate cells shows elevated EPCA levels, this would indicate that prostate cancer exists - even if the needle samples didn't find it. "But the absence of EPCA staining would reveal that there is no prostate cancer within the gland," Getzenberg continues, and the patient can relax, knowing he doesn't need to have another biopsy right away.

"Which men have prostate cancer with the potential to kill them, and which men have prostate cancer that is more like a pussycat?"

Getzenberg and colleagues have also developed an EPCA blood test, to go along with the PSA test, that can help doctors figure out what's causing the PSA to rise - namely, whether it's cancer, or another prostate problem. The EPCA blood test is "highly specific for prostate cancer," he says. "Men with elevated EPCA levels have about a 90- to 95-percent chance of having prostate cancer." Clinical trials for this EPCA blood test have already been conducted, and a larger study is now under way.

Is the cancer slow-growing, or aggressive? "Which men have prostate cancer with the potential to kill them, and which men have prostate cancer that is more like a pussycat?"Getzenberg has developed a test to help determine this, using a new, blood-based prostate cancer marker (one of several he's testing) called EPCA-2. "We have evidence that EPCA-2 appears to be elevated at its highest levels in men with most aggressive forms of the disease." However, EPCA-2 shows up at much lower levels in men with less aggressive cancer. EPCA-2 is now being tested inclinical trials.

BPH, like cancer, can be "good" or "bad." Benign enlargement of the prostate (BPH), doesn't just affect the prostate, and it isn't always benign. It affects the bladder, and in severe form, its symptoms can be debilitating. "Until recently, all BPH was considered to be a single disease," notes Getzenberg. But his research group has found a genetic marker, called JM-27, that's associated with the most aggressive type of BPH. Further, Getzenberg and colleagues have developed a blood test that can determine whether a man has the most severe form of BPH, or whether his case is mild. They hope that this test will even be able to predict how a man will respond to various treatments of BPH. "This is the first BPH-specific marker that has been identified, and we hope it will play a role in how men are treated for the disease," he says.

Markers for bladder cancer: Getzenberg's search for markers has extended to bladder cancer. "Bladder cancer is the second leading urologic cancer, and it has increased significantly over the past couple of years," he explains. He and colleagues have identified several novel markers for bladder cancer, and have developed a simple urine test for one of these, called BLCA-4. BLCA-4 may have other uses, as well: It appears to regulate gene expression within the bladder, and also to affect certain proteins that may be important in the development of the disease. Getzenberg and colleagues have developed a similar urine test for another marker, called BLCA-1, and hope to combine these two as says in clinical studies. These markers are being tested in a large clinical trial of more than 3,000 patients.

BPH and cancer - any connection? BPH and prostate cancer affect different regions of the prostate, but they're both associated with aging. They may have other things in common, as well, says Getzenberg. "We have identified a series of genes that appear to be altered in both BPH and prostate cancer. There may be much more connection between BPH and prostate cancer than we originally envisioned. Understanding more about the development of each of these diseases will help us develop better tools with which to attack them both."


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