A Ruthless Foe
With dynamic weapons and creative new tactics,
USC scientists are launching fresh assaults on prostate cancer.
by Janet Farrar Worthington
For Fred Parrott, hell is the nightmare of watching your father die slowly from prostate cancer diagnosed too late; feeling all the more helpless by knowing that, even though you are a physician, you can do nothing to save him.
Hell, Part Two, is receiving the same diagnosis 20 years later and believing you are going to die, too.
Says Parrott, 67, a retired Los Angeles gynecologist: "I was so devastated. I assumed this was a death sentence, so I made out my will."
Parrott had not confronted the possibility that he might also be at high risk for prostate cancer until 1992, when a friend was treated for an enlarged prostate. Parrott had a prostate biopsy. It was negative; his urologist did not order a PSA blood test, so Parrott ordered his own. PSA- prostate-specific antigen-is an enzyme made by the prostate and an indicator of prostate cancer. The reading was 4, on the high end of what is generally considered normal for a man of his age. In 1993, he ordered another; it had risen to 6.2. This time, the biopsy found cancer. Parrott came to the USC/Norris Comprehensive Cancer Center, where he underwent removal of his prostate, performed by urologist Eila C. Skinner, M.D.
That was three years ago. Fred Parrott did not die. "Early detection saved my life," he says. "It can save other lives, too." (See "Real men reach out," page 12.)
The advance of prostate cancer can be stopped with surgery and radiation therapy. Surgery is light-years beyond what it used to be: an operation where there was extreme bleeding that collected in the area of the prostate. Surgeons had to blindly feel their way, damaging tiny, vital nerves which eventually caused loss of urinary control and the ability to achieve an erection. Because of these side effects, many men wondered which was worse-having the cancer or having the operation. Now, there is a surgical technique that lessens the amount of bleeding so skilled physicians are able to save crucial structures that previously they could not even see. Dubbed the "Walsh procedure" after its inventor Patrick Walsh of the Johns Hopkins Hospital in Baltimore, Maryland, Skinner performs this nerve-sparing procedure, which makes surgery infinitely safer. According to Skinner: "Now, cases of incontinence and impotence are the exceptions, rather than the rule."
But prostate cancer must be stopped before it creeps beyond the prostate and establishes itself elsewhere. Once it metastasizes, the spread of prostate cancer is merciless. Its progress may be delayed for months or even years, but its advance cannot be halted. The statistics are sobering: This year in the U.S., an estimated 317,000 men will be diagnosed with prostate cancer. More than 40,000 men will die from it.
Men over 50 should get a yearly PSA blood test and digital rectal exam, says Skinner. Men with the highest risk-those with a family history of the disease, particularly a brother, and all African-American men-should begin this yearly cancer-screening even earlier, at age 40.
At present, early detection and treatment for cancer that has not yet spread are the most successful weapons in the fight to curb prostate cancer mortality.
This may soon change. USC scientists are marshaling new weapons for fresh assaults. They are exploring the origins of prostate cancer at the genetic level; they are testing new drugs aimed at slowing or halting the progress of advanced cancer, and they are developing elegant strategies to help currently available drugs-and the body's own immune system-subdue prostate cancer cells.
PRONE TO PROSTATE CANCER
In epidemiologic studies begun two decades ago, Ronald Ross, M.D., the Catherine and Joseph Aresty Chair for Urologic Research, professor of preventive medicine, and associate director of the USC/Norris Cancer Center, was among the first to realize that prostate cancer strikes some groups of men much harder than others. "African-American men have by far the highest prostate cancer rates in the world," he says. "At the other end of the spectrum, Japanese and Chinese men have the lowest rates of prostate cancer." Although environmental factors such as diet undoubtedly play a role, USC/Norris scientists believe the keys to these differences must lie in the genes.
Ross began his landmark research with a premise: The prostate-a gland about the size of a walnut-is regulated by sex hormones called androgens. One of these is testosterone, which circulates in the blood, seeps into the prostate, and is changed into dihydrotestosterone-DHT. DHT is a major influence on the production of proteins released by the cells in the prostate. Androgens are pivotal instigators of cell division in the prostate, and Ross believes that the number of times cells divide is critical for the development of cancer. Ross and his colleagues began looking at the hormonal make-up of healthy men in various racial-ethnic groups. Their studies suggested that all men's hormones are not alike: Some men make hormones in different quantities and combinations than other men. Others process, or metabolize, them differently. And hormones themselves differ in activity from one man to another.
Ross and his colleagues decided to focus on five genes that are important in hormone regulation-and thus involved in, among other things, triggering cell division in the prostate. According to Ross, the arrangement of these five genes varies among individuals and population groups, so some genes might be of greater importance in the cancer process in certain men and less so in others. Ultimately, the scientists hope to figure out the relationships of these genes to each other, and discern their roles in prostate cancer. They also hope to explore other environmental factors, like diet and exercise, to see whether different foods or more exercise can lower prostate cancer risk.
PROSCAR AND PREVENTION
One outgrowth of Ross's work is a large study to see whether a drug already used to treat benign enlargement of the prostate (a noncancerous but annoying condition that affects older men) can stop prostate cancer from forming. The drug, Proscar, a brand name for finasteride, manufactured by Merck Pharmaceuticals, works by blocking the production of an active form of testosterone in the prostate. Skinner, who heads the study at USC, hopes to determine whether shutting off testosterone metabolism in the prostate will stop cells from dividing, and whether in "doing this, you can decrease the chances for development of cancer." In addition, this once-a-day drug does not cause impotence or other undesirable side effects that result from a lack of testosterone.
In all, 18,000 men aged 55 and over will be tested nationwide in the seven-year study. The men, who will be screened first to make sure they are in good health and have a normal PSA, will receive either Proscar or a placebo. Another Proscar study, headed by Skinner, will follow patients with an elevated PSA but a negative biopsy. All the men will be observed, with some receiving Proscar. They all receive a second biopsy one year later.
While the theory behind the Proscar treatment is sound, Skinner says "because cancer is a complex process, there is a possibility that Proscar will not be effective."
WHEN CANCER HAS SPREAD
Fred Parrott was lucky. His cancer was caught in time. But what if, when he went for that physical, the cancer had already metastasized?
This is where the research of Ronald Natale, M.D., enters. Natale, head of the Genitourinary Cancer Program at USC/Norris, divides his time between the present-fine-tuning current treatments and testing new drugs for metastatic prostate cancer-and the future-helping develop innovative ways to attack prostate cancer at its most basic levels.
One drug he is testing is suramin, manufactured by Warner Lambert Parke-Davis, a promising chemotherapy drug with the ability to kill cancer cells by disrupting several of their growth dependent processes. Another drug Natale will test is a new form of doxorubicin, encapsulated in a fat globule, which seems to make it more effective in killing prostate cancer cells.
Natale is also working on an immunotherapy approach with USC medical oncologist Jeffrey Weber, M.D., Ph.D. "We hope to start a trial where we will vaccinate men to prime their immune system so that it reacts against either PSA or PSMA (prostate-specific membrane antigen) proteins, which are produced by normal and cancerous cells in the prostate," says Natale. Because the body ordinarily recognizes both PSA and PSMA as being normal cell products, the immune system does not react against them. "We are going to try to re-engineer how PSA and PMSA are presented to the body-we will basically trick the immune system into recognizing them as enemies and rejecting them."
Natale is also collaborating with USC molecular biologist Gerhard Coetzee, Ph.D., on an innovative strategy to apply the burgeoning science of gene therapy to prostate cancer. In normal and cancerous cells in the prostate, the genes that regulate the synthesis of DNA are operated by switches called androgen-response elements, or AREs. Normally, androgens must bind to androgen receptors to turn these switches "on." But in prostate cancer cells, mutated androgen receptors keep these switches turned on continuously. What Natale and Coetzee hope to do is use these mutated androgen receptors as genetic Achilles' heels-potential chinks in the formidable armor of prostate cancer cells.
Their secret weapon is a "molecular bomb." In theory, Natale explains, "We inject this molecular bomb-a herpes gene hooked to an ARE and mounted on a specially designed viral delivery vehicle-into the bloodstream, where it can get into dividing cells in the body. The only cells able to trigger the molecular bomb are the prostate cancer cells because only they contain the mutated androgen receptors that can activate the ARE. We then administer an anti-herpes drug that kills the cells containing the herpes gene, thereby destroying only the prostate cancer cells." In other words, they will be killing the prostate cancer cells which contain the herpes gene using an anti-herpes drug.
These types of techniques may be the prostate cancer treatment of the future. Meanwhile, the best hope for today remains early detection. Which brings us back to Fred Parrott, prostate cancer survivor. Actually, it brings us to his answering machine, which carries this message:
"Top of the morning. Prostate cancer is a devastating disease for men. Please call five men today and encourage them to be tested. It may save their lives."
To participate in the Prostate Cancer Prevention Trial, call research nurse Susan Mertes at (213) 764-3753. For more information on the prevention and treatment of prostate cancer, call 1-800-USC-CARE.
RELATED STORY: REAL MEN REACH OUT
For reasons still not understood, in this country prostate cancer strikes an estimated one out of every eight African-American men, compared with one in 11 Caucasian men.
It did not take prostate cancer survivor Fred Parrott long to come up with the idea of helping other men beat these odds. When his surgeon, Eila Skinner, M.D., came into his hospital room to tell him the good news-that she believed she had removed all the cancer-Parrott says, "The next thing that came out of my mouth was, 'Let's take this to the inner-city.'"
Skinner liked the idea; her boss, Donald Skinner, M.D. (no relation), chair of the USC Department of Urology, pledged staffing and resources to the program, the basic structure of which was already in place: The Real Men Cook Foundation. Created in 1988 by Parrott (and named for the cook-offs the organization holds to raise money) as a means of supporting African-American medical students, the Foundation redirected its mission toward cancer screenings.
Since 1994, the Foundation has provided free, confidential screenings for nearly 1,200 men, Parrott says, "most of them inner-city, mostly African-Americans." Adds (Eila) Skinner, who became the Foundation's medical director: "We've detected a number of cancers and had patients come back the second year for follow-up. It has been a tremendous program."
Parrott has tirelessly pounded the pavement, talking to about 5,000 men in his estimation, persuading local ministers to spread the word, and distributing fliers. "I think the Lord saved my life and gave me a mission," he states, "and that is to increase awareness of prostate cancer among men."
Still, it is not enough, says Parrott, who manages brilliantly on what- despite donated time, supplies and office space- is truly a shoestring budget. "In general, prostate cancer research is under-funded. But with everyone's help, we'll make it better."