A Publication of the James Buchanan Brady Urological Institute Johns Hopkins Medical Institutions

An Epidemiologist Comes to the Brady

Bruce Trock: "How do variations in treatment affect a man's quality of life? How do the symptoms that he experiences afterward affect it?"

Like fingerprints, cases of prostate cancer differ from man to man, depending on many particulars-his age, for instance, or PSA, or even the ratio of cancer cells that are nourished by male hormones, compared to those that aren't. It's a terribly individual disease. So why is Bruce Trock, Ph.D., so interested in looking at the bigger picture?

Because he's an epidemiologist. Actually, he's the first of a first-the new director of the Brady Urological Institute's brand new division of Epidemiology, the first of its kind in any urology department in the country; the division was launched by a gift from philanthropists Helen and Peter Bing. And epidemiology, Trock explains, is the connection between basic science and the clinic. "A scientist like Bill Nelson or John Isaacs might be looking at something in the lab-a new marker for detection, or a preventive agent, or a risk factor-or examining 30 specimens of prostate tumor and measuring something. We examine it in 300, or 500, or 1,000 people, so we can find out whether it works differently in older men than younger men, in black men versus white men, in men who have a family history versus those who don't. All of these aspects are important in how the disease actually manifests itself in the population."

Men who die from prostate cancer have more cadmium in their prostate than other men. And of all the body's organs, guess which one has the highest concentration of cadmium? The prostate. Apparently, once cadmium enters the body, it stays put.

So many variables, and so many different groups of men-who make up the word epidemiologists love to use, "populations." "That's part of the challenge," says Trock. "It's like a puzzle, a detective story. How do the pieces fit together?"

Trock, who came to Hopkins from Georgetown University, "brings unique strengths that enhance our translational research efforts," says Urologist-in-Chief Patrick C. Walsh, M.D. Trock's distinguished research-in cancer of the breast as well as the prostate-has made important contributions to the understanding of diet and breast cancer. Trock also made the first comprehensive assessment of a particular gene, called the multi-drug resistance gene, to show that it is commonly expressed in breast cancer, and is a strong predictor of resistance to chemotherapy. "It's unusual to find someone with strong credentials in epidemiology and biostatistics who can successfully bridge his work with clinical and basic science," says Alan Partin, M.D., Ph.D., Bernard Schwartz Distinguished Professor of Urologic Oncology, who recruited Trock to Hopkins, and who will be working with him on many projects.

Trock's research at Hopkins is focused on four major areas:

Causes. What sparks prostate cancer? How do environmental or dietary exposures cross-pollinate with the body's basic gene makeup? "We're looking at oxidative damage, at diet, at what normal processes of the body, normal function of the prostate, and normal aging of the prostate make it susceptible to cancer," says Trock.

He's also zeroing in on exposure to cadmium. "Some studies have shown that men in certain occupations, with higher levels of exposure to cadmium, have a higher risk of prostate cancer." Laboratory rats that are given cadmium are known to develop prostate cancer, and cadmium has been shown to mimic some effects of male and female hormones. "Cadmium interacts with the hormone receptors in a way that's similar to estrogen or testosterone," says Trock. "So it's possible that it can stimulate growth of the prostate in an abnormal way." Cadmium also may push beneficial zinc out of the prostate. Autopsy studies have shown that men who die from prostate cancer have more cadmium in their prostate than other men. And of all the body's organs, guess which one has the highest concentration of cadmium? The prostate. Apparently, once cadmium enters the body, it stays put. "It's very metabolically inert," Trock explains. "You can get cadmium in your body, and it will stay there for 20 years."

Baltimore is a natural for studying cadmium exposure-it's an issue for men who build and repair ships, welders, men who work in canning factories, men who are exposed to paints, and a risk of soldering, galvanizing, and electroplating. "We're mapping the city for areas that potentially had higher cadmium exposure. Then we'll take the highest-exposure zip codes, and whenever a man comes here to be biopsied for prostate cancer, if he's from one of those zip codes, we'll take a sample of his biopsy. With the men who turn out to have cancer, we'll see whether they have more cadmium in their prostates than the men who didn't."

Clinical biomarkers. Trock is interested in tapping (literally) a largely unexplored area in prostate cancer research-prostatic fluid. In the past, it was difficult to obtain prostatic fluid for examination. However, today it is easily collected from surgical specimens.

One of the prostate's main jobs is to contribute a bit of fluid to the mixture that makes up semen. "Prior to ejaculation, the sperm are kept in an inactive form," explains Trock, "they don't have much movement. But when they mix with the prostatic fluid, that seems to activate them and make them move around a lot, so they are ready to seek out the egg." There's an abundance of reactive oxygen in semen and prostatic fluid, and "a lot of research in fertility that's looking at the effects of oxidative stress on the viability of sperm. So we know that oxidative stress is being generated in that process. Is any of that affecting the prostate? Does this over time lead to some sort of irritation or inflammation? Are certain groups of men more susceptible to this, perhaps men with lower levels of a protective enzyme, or lower levels of dietary antioxidants?" Trock also believes that studying the prostatic fluid can shed light on normal aging of the prostate.

Chemoprevention. Does eating spaghetti several times a week somehow help prevent prostate cancer? Does broccoli make your body more cancer-proof? Trock is ready and able to investigate, taking advantage of the many compounds being identified and studied in Brady laboratories. "There's the potential to do relatively quick studies with these," says Trock. One easy, short-term period for testing a chemopreventive agent is the time between a man's diagnosis with prostate cancer and radical prostatectomy. The removed prostate is then compared to the "before" snapshots of the needle biopsy, to see if anything's changed, "if something is altered in a way that suggests there would be a lower risk if the man didn't already have the disease," Trock explains. "Are we decreasing the growth rate of the cells, decreasing PSA, enhancing the level of normal cell death? All of these can be measured with what we call surrogate endpoint biomarkers.' They tell us if we're altering the biology in a beneficial way, and provide insight into what we really want to know, which is, Does it change the risk?"

Quality of life. Ideally, a man's cancer is diagnosed early, he's treated at a "high-volume" center-a place like Hopkins, where radical prostatectomy is done every day- by an experienced surgeon. He has minimal side effects, then it's over. He gets his life back, and the whole thing, from biopsy to recovery, is just a "blip" on the radar screen of his life. But for many men, this doesn't happen. "How do variations in treatment affect a man's quality of life? How do the symptoms that he experiences afterward affect it?" It's hard enough comparing surgery patients to surgery patients, harder still comparing these men to men who have undergone radiation therapy. "There are many papers that compare results in men who've had radiation to men who've had prostatectomy," says Trock, "but in fact, those are not comparable. There are many differences that come into play-particularly, different ways to compute survival rates in one group compared to another. So how can you get a valid comparison, short of doing a trial where you randomly assign some men to radiation, and some to prostatectomy?" Lars Ellison, a Robert Wood Johnson research scientist, will collaborate with Trock on a study of men who receive treatment at nationally recognized "centers of excellence" for radiation or radical prostatectomy.

In the most ambitious project so far, Trock is one of several scientists planning a super-sized study, involving possibly 100,000 Baltimore-area men and women. One major focus would be prostate cancer risk, side effects, progression, and prognosis. "There are a number of these very large-scale cohort studies, but none with a heavy urban component. We're going to be looking at a population that's representative of Baltimore-a high representation of African American men, men in other ethnic groups who have different levels of prostate cancer risk. This will encompass Brady, the Kimmel Cancer Center, the School of Hygiene and Public Health, and it will be going on for 10 to 20 years."


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