A “Win Win”

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					P R O S TAT E                                           C A N C E R

The Br ady Urological Institut e                               •   Johns Hopkins Medicine

 A P U B L I C A T I O N O F T H E PA T R I C K C . WA L S H P R O S T A T E C A N C E R R E S E A R C H F U N D
                                                                                                                                   VOLUME I • WINTER 2005

                                                                                                                           T H E PA T R I C K C . WA L S H
                                                                                                                     PROS TATE C ANCER RESEARC H FUND

                                                                                                                     F O U N D E R S’             C I R C L E
                                                                                                                                 Anonymous (3)
                                                                                                                        Mr. and Mrs. Robert B. Aikens
                                                                                                                         Mr. and Mrs. Robert C. Baker
                                                                                                                               Family Foundation
                                                                                                                            Mary Ann & Bill Becker
                                                                                                                          Dr. and Mrs. Peter S. Bing
                                                                                                                              Jennifer A. Chalsty
                                                                                                                                John S. Chalsty
                                                                                                                         The Deeks Family Foundation
                                                                                                                            R. Christian B. Evensen
                                                                                                                          Phyllis and Brian L. Harvey
                                                                                                                         Heather C. and Patrick Henry
                                                                                                                      Charlton C. and F. Patrick Hughes
                                                                                                                        Beverly A. & Gary L. McDonald
                                                                                                                          Beth W. and A. Ross Myers
                                                                                                                              Nancy & Jim O’Neal
                                                                                                                          Mr. & Mrs. Paul W. Sandman
                                                                                                                       The Peter Jay Sharp Foundation
                                                                                                                        Irene and Bernard L. Schwartz
                                                                                                                            Carolyn and Bill Stutt
                                                                                                                     Mr. and Mrs. Charles B. Thornton Jr.
Partin: “I am excited to have the opportunity to guide the ship.”                                                           Luciana & Joe Vittoria

A “Win-Win”                                               Professor of Urology. He is the editor of
                                                          Urology, one of the specialty’s top two jour-
                                                                                                                   The Patrick C. Walsh
Partin is New Director; Walsh                             nals, the author or co-author of more than               Prostate Cancer Research
                                                          350 papers, and the recipient of notable
Devotes Time to Surgery                                   honors, including an award by the American               Fund: The Winning
There’s good news, and good news. First,                  Urological Association, given yearly to the
                                                          urologist who has made the greatest impact
                                                                                                                   Vision Continues
although Patrick C. Walsh, M.D., has
stepped down from his administrative                      within the first 10 years after completing his           This first issue of Prostate Cancer Discovery
responsibilities as Director of the Brady                 residency. Partin was the first urologist to             marks the fruition of The Patrick C. Walsh
Urological Institute, he isn’t going anywhere:            receive this honor after only five years of              Prostate Cancer Research Fund, spearheaded by
Now he will devote his full time to patient               practice, and he was the youngest urologist              the Brady Advisory Council, and made possible
care, surgery and research. The other good                to be inducted into the prestigious Ameri-               by many of Dr. Walsh’s patients, their families
news is that the Brady is in excellent                    can Association of Genitourinary Surgeons.               and friends.
hands—the hands of renowned urologist                        The work that has made him famous, and                   After three decades at the helm of the Brady
and scientist, Alan W. Partin,                            earned him such awards, is the eponymous                 Urological Institute, Dr. Walsh has stepped down
M.D., Ph.D., Bernard Schwartz Distin-                     set of tables that has given thousands of men            from his administrative responsibilities as Direc-
guished Professor of Urologic Oncology.                   with prostate cancer worldwide a 95-percent              tor to devote more time to patient care, surgery
   This is a job, Partin says, that he’s                  accurate prediction of their likelihood of               and research. In developing the fund that bears
dreamed of for years. “I am excited to have               being cured by treatment. The Partin Tables              his name, the Council has made certain that his
the opportunity to guide the ship. We have                were developed at the Brady in 1993 by Partin            winning approach to the prevention, treatment
an excellent group of people here, all doing              and Walsh, after Partin studied the course of            and ultimate cure of prostate cancer will carry
wonderful things.” Partin is a Hopkins-                   prostate cancer in hundreds of Walsh’s radi-             on. All of us waging this war against prostate
trained doctor and scientist. He learned to               cal prostatectomy patients. The tables corre-            cancer—working to end the havoc of the disease,
perform urologic surgery under Walsh’s                    late three key pieces of the prostate cancer             and to prevent our sons and grandsons from ever
tutelage, and as he earned his Ph.D., his                 puzzle—a man’s PSA, Gleason score, and esti-             developing it—believe that the cure for prostate
mentor in molecular pharmacology was                      mated clinical stage—with the actual patho-              cancer will be found soon, and it will be found
Donald S. Coffey, Ph.D., the Catherine                    logic stage, determined when pathologist                 here. The Advisory Council, and all who have
Iola and J. Smith Michael Distinguished                   Jonathan Epstein, M.D., [continued on page 2]            given to the Fund, strongly [continued on page 2]
2 PROSTATE CANCER DISCOVERY                                 WINTER        2005

[continued from page 1]                                 Partin plans to recruit faculty with other                an option for treatment here.”
                                                        research interests, as well, including:                • Endourology—stone disease. “We need to
examined the surgically removed prostate                • Female urology, with a focus on such issues             focus attention on the art and clinical care
specimens. Revised and expanded over the                   as overactive bladder and incontinence.                of patients with stone disease. For many,
years, the tables have become an indispensa-            • Inflammatory and infectious diseases of                 it’s a lifelong disease, with a lot of issues.”
ble tool for doctors and patients.                         urology, such as pelvic pain, interstitial          Partin is also determined to increase the
   That Partin will continue doing this and                cystitis, and prostatitis. In addition to           Brady’s physical size. “The Brady Urological
other research (one of his studies is featured             expanding our knowledge of these dis-               Institute in the Marburg Building has
on page 6), and keep seeing patients and                   eases, Partin says, we need further explo-          expanded far beyond its walls,” he notes, “to
performing surgery, as well as carrying on                 ration of the emerging link between                 include research space in the Cancer Research
his editorship of Urology, is characteristic; he           inflammation and prostate cancer (see               Building, the Oncology Center, and the Pedi-
has a knack for being able to handle many                  story, page 4).                                     atric Building.” He is working to acquire
projects simultaneously, and to do them                 • Reconstructive surgery, including urethro-           enough space within the Hospital “to bring
well. He wants the same for the Brady—to                   plasty and pelvic floor reconstruction.             some of this back together, to consolidate it
keep doing what it’s doing at the same stan-               “We will strengthen our collaboration               within one area, and continue to grow over
dard of excellence, and to do more. “We are                with general surgery and gynecology, with           the next 20 years.”
going to continue our mission,” he says.                   our role in the new Pelvic Floor Recon-                One of Partin’s first challenges will be to
“We have held our position, of being                       structive Center” at the Johns Hopkins              replace another longtime Brady legend who
(ranked by U.S. News & World Report) the                   Bayview Campus.                                     seems irreplaceable—his mentor, Don Coffey,
Number One in urology, 14 years in a row.               • Pediatric urology research and clinical care.        who is stepping down as the Institute’s
We’re going to continue to foster that in the           • Nonsurgical treatments of prostate cancer.           research director. Coffey’s shoes are so big for
strongest way.” Urologic oncology—especially               “We are expanding the menu for treat-               one person to fill that Partin isn’t even going
in prostate cancer—is so strong at the Brady,              ment of men with early-detected, clinically         to try. “We are going to have two research
Partin adds, but he wants to fortify the                   localized prostate cancer, through collab-          directors,” he explains, “one for basic science,
Institute’s efforts in research and clinical               orative efforts with the Department of              and one for translational research—moving
care of other cancers, including the bladder,              Radiation Oncology,” says Partin, “so               those discoveries from the laboratory bench
kidney, and testes, by recruiting internation-             men who aren’t interested in surgery or             to the patient’s bedside, as quickly and as
ally recognized scientists in those areas.                 external-beam radiation therapy will have           seamlessly as possible.”

[continued from page 1]                                 Applications will be reviewed by a scientific
                                                        advisory board, led by Dr. Walsh and made up of         Walsh Wins Top Honors
                        embrace the concept             Hopkins faculty and two laypeople—patients
                                                                                                                In recent months, Patrick C. Walsh, M.D., has
                        behind the world-class          who are knowledgeable about the management
                                                                                                                received some of the highest honors in urology
                        research program that Dr.       and treatment of the disease, as well as the most
                                                                                                                the world has to offer. These include:
                        Walsh has created—one           current research. Grants, ranging from $50,000 to
                        that is unique in its depth,    $100,000, will be awarded each year to the most         • The Ramon Guiteras Award, the highest
                        scope, and multidiscipli-       promising research initiatives.                           honor bestowed by the American Urological
                        nary approach.                      The Walsh Fund is off to a powerful start.            Association
                           Dr. Walsh believes that      More than $25 million has been rasied so far to         • The Charles Huggins Award, the highest
                        victory in this war hinges      provide critical support. The latest commitment           honor given by the Society of Urologic
Patrick C. Walsh        on a many-sided assault—        came as a surpise when Founders’ Circle mem-              Oncology
our version of the Army, Navy, Air Force and            bers, Beth and Ross Myers, doubled their previ-         • Honorary Membership in the Royal College
Marines. Soldiers fighting a battle don’t aim to win    ous contribution for a total gift of $2 million at a      of Surgeons of Ireland
just a few isolated skirmishes; their goal is “defeat   celebratory event honoring Peg and Pat Walsh.           • Honorary Membership in the Royal College
in detail”—winning on every front. With this in         The first grants will be awarded in the Spring of         of Surgeons of England, and
mind, Dr. Walsh has enlisted and supported basic        2005. We will report the latest news from the           • The John Carroll Society Medal
scientists, medical and radiation oncologists, and      frontlines of the research supported by the Fund        In addition, the major textbook of urology has
pathologists to work with urologists in finding         in future issues of Prostate Cancer Discovery. On       been renamed in Walsh’s honor. For the last
new pathways, and developing more sophisticated         the front page of this newsletter are the names         25 years, Walsh has been the senior editor
weaponry to penetrate prostate cancer’s defenses.       of the Founders’ Circle members, donors who             of Campbell’s Textbook of Urology, widely
   Continuing this vision, the Walsh Fund will          have given $500,000 or more in their commitment         considered to be the “bible” of urology world-
make it possible to attract and recruit the bright-     to defeating prostate cancer. Also inside this          wide. The textbook, which has expanded
est scientists from all disciplines at Johns            issue are the names of all of the people (as of         over the years to encompass four volumes
Hopkins to focus their efforts on prostate cancer.      press time, October 30, 2004) who have given so         and 4,000 pages, will now be named the
Each year, a request for proposals will be sent         generously to help in this effort. If you are inter-    Campbell-Walsh Textbook of Urology.
to every Johns Hopkins scientist; we will cast          ested in becoming a part of this groundbreaking
the net widely, to secure fresh, innovative ideas.      work, please call (410) 516-6160.
                                                                          WINTER        2005       PROSTATE       CANCER         DISCOVERY           3

NOW ON DVD, FOR FREE                             out inadvertently damaging the fragile nerves.          With the financial help of the Mr. and
                                                 An experienced surgeon, too, can tell much by       Mrs. Robert C. Baker Foundation, the
The “Gold Standard”                              tactile sensation—literally, feeling the tissue     DVD was mailed with four major journals
                                                 for hardness, adherence, or other signs of          to 40,000 urologists around the world. An
Treatment for                                    cancer, and deciding how best to remove it. A       additional 15,000 copies are available for
                                                 very experienced surgeon has a “Plan B” if one      free, for any urologist who wants one. “I
Prostate Cancer                                  man’s anatomical terrain is                         could have gone to a drug company and
                                                 slightly different from                             asked for financing,” explains Walsh, “but
“Nerve-sparing” radical prostatectomy—the        most. For example,                                     then they would have control of it, and
operation devised by Patrick C. Walsh, M.D.,                                                              over who sees it. I wanted to have some-
and continuously refined by him over the                                                                    thing I could give to everyone in the
last 20 years, in more than 3,000 patients—                                                                  world, including doctors in developing
has been in many ways a double-edged                                                                         countries.”
sword. In the hands of Walsh, and the                                                                           It’s worth noting that a century
dozens of urologic surgeons he has trained                                                                   ago, on April 7, 1904, the very first rad-
over the years, the operation preserves the                                                                 ical prostatectomy was performed by
delicate, microscopic nerves, which are neces-                                                             Johns Hopkins urologist Hugh Hamp-
sary for erection, that sit on either side of                                                            ton Young. That operation laid the
the prostate—but also removes as much                                                                groundwork for the “nerve-sparing” proce-
tissue as possible around the cancer. At the                                                         dure that Walsh first performed in 1982. And
Brady Urological Institute, the high rates for                                                       Walsh continues to improve the operation—
cancer control and potency, and the very low                                                         “I’m at the top of my game,” he says. He is
incidence of incontinence and other side                                                             sharing what he knows because he believes it’s
effects, are used as the “gold standard,”                                                            the right thing to do: “If you’ve been given the
against which all other forms of treatment       Walsh’s “magnum opus,” the free, 105-minute         privilege of sailing in uncharted waters, you
are compared worldwide.                          DVD for surgeons, was five years in the making.     have the responsibility to make those charts.”
   This is also the only form of treatment
for localized prostate cancer that has been      in 4 percent of patients, the arteries that
shown to prolong life. In a landmark Scandi-     supply the penis travel immediately over the
navian study, men with localized prostate        prostate. Unless the surgeon knows how to           Nerve-Sparing
                                                 preserve the blood supply in this particular
The Walsh procedure is notoriously
                                                 situation—and unfortunately, very few               and Positive
                                                 surgeons do—the man will be impotent.
difficult to perform. “He makes it               With Help from a Patient
                                                                                                     Surgical Margins
look easy, but believe me, it’s not.”            How do you handle the lightning bolt of             What happens to the nerves responsible for
                                                 discovery—especially when you’ve seen its           erection if cancer has escaped the prostate?
                                                 great potential to help people? Well, you           Can they still be preserved? Sometimes,
cancer were randomly assigned either to the      could guard it jealously, like the proverbial       cancer ventures only slightly beyond the
Walsh technique of radical prostatectomy or      dog in the manger, expressing dismay that           prostate—a distance significant enough for
to watchful waiting. Within as little as eight   other hospitals’ results aren’t nearly as good      the surgical margins, the edges of the
years, twice as many men in the watchful         as yours. Or, you could do your best to share       removed tissue, to be considered positive,
waiting group had metastatic cancer in the       what you know—and this is what Walsh has            but really just a matter of a couple of mil-
bone, and twice as many had died of prostate     done, with the help of a remarkable patient,        limeters. If this happens near the neurovas-
cancer. In this study, the “Walsh procedure”     Robert Baker.                                       cular bundle, one of two tiny packages of
reduced prostate cancer deaths by about half.       Walsh has put everything he knows about          blood vessels and nerves adjacent to the
   But—and here’s the other edge of that         this procedure onto a free, 105-minute DVD          prostate that are responsible for erection, is
sword—the Walsh procedure is notoriously         for surgeons. On the DVD, which has been            that bundle automatically doomed?
difficult to perform. “He makes it look easy,”   five years in the making—and which he calls            Not necessarily, says Patrick C. Walsh,
notes surgeon Alan Woolfenden, of the Royal      his “magnum opus”—are detailed descrip-             M.D. “When cancer spreads microscopically
Liverpool University Hospital, who recently      tions of each step of the operation, including      outside the prostate, the tumor rarely
came to Hopkins to watch Walsh perform the       close-up video footage of intricate dissection,     extends more than one or two millimeters
operation, “but believe me, it’s not.” For any   suturing and reconstruction, and stunningly         into the adjacent soft tissue. This is because
surgeon, this procedure—technically, the         detailed illustrations by Hopkins medical           cancer cells seem to need the environment of
anatomical radical retropubic prostatectomy—     artist Juan Garcia. “You won’t see this kind        the prostate.” Walsh uses the example of
is a bumpy, treacherous road. There can be       of illustrations in Gray’s Anatomy,” says Gar-      seeds and soil: “The soil is the tissue of the
extreme blood loss. It takes years of training   cia. (Many of these illustrations and some          prostate, and the seeds are the prostate can-
before a surgeon can handle the unexpected       video clips from the DVD are available on           cer cells. If they spread without the proper
bleeding without panicking—and also with-        the Brady website, at      soil, they can’t survive.”
 4 PROSTATE CANCER DISCOVERY                               WINTER       2005

    Prostate cancer cells can eventually learn
 to make a habitable environment outside the
 prostate, but this process is complicated and
 can take years, he adds. (A lot has to do with
 the Hedgehog pathway—see story, page 12)
    In a recent study, urology resident David
 Hernandez, M.D., along with pathologist
 Jonathan Epstein and Walsh, reviewed 100

“It takes a great deal of experience,

 and also tactile sensation, in

 determining exactly when and

 where it is possible to preserve the

 neurovascular bundle, and where

 it is necessary to remove it”.

                                                       Multidisciplinary “Dream Team:” Nelson, De Marzo, and Isaacs, along with a laser capture microscope that
 men who had evidence of extension of                  was funded by the Peter Jay Sharp Foundation. With this advanced instrument, scientists can collect DNA
 cancer outside the prostate, in the area of           and RNA from the nuclei of individual cancer cells, and find the genetic fingerprint for prostate cancer.
 the neurovascular bundle. During surgery
 Walsh, who has long respected the use of
 tactile sensation—what he can feel of the
 prostate and surrounding tissue—during the            What Does                                             answer—are revealing unexpected cracks in
                                                                                                             the citadel. Their work so far, recently
 operation, determined that it was safe to
 preserve the nerve bundle in 84 of the men.           Inflammation Have                                     summed up in a landmark paper in the New
                                                                                                             England Journal of Medicine, has identified a
 He excised the bundle and surrounding tis-
 sue in the remaining 16 men.                          to Do With Cancer?                                    new target—which may, in fact, be the
                                                                                                             “smoking gun” that causes prostate cancer.
    Later, when Epstein examined the removed
 surgical specimens, he found that the fre-            Trio Closes in on                                     Methylation: Silencing genes
 quency of positive margins was only 5.8 per-
 cent—six men. This low rate of positive surgi-
                                                       “Smoking Gun”                                         For the last decade, Bill Nelson has been
                                                                                                             looking at what we eat, what we don’t eat,
 cal margins is essentially the same as Walsh          Imagine a movie about a great adventure—a             and trying to figure out what we should eat.
 achieves in all of his patients. It is also identi-   bold jewel heist, a daring escape—and con-            His pioneering work on the role of diet in
 cal to the number of positive surgical mar-           sider the characters. There’s the demolitions         prostate cancer has shown that oxidative
 gins reported by another urologist—except             expert, the safe-cracker, the code-breaker—all        damage to DNA—incremental damage
 that urologist widely excises the neurovascu-         specialists, who tackle one facet of a job that       accrued as carcinogens hammer away at our
 lar bundle in 65 percent of his patients.             looks to be impossible. This kind of multi-           genes, like invaders with tiny battering
    Of the 100 men in this study, 86 percent           disciplinary team is the Walsh Fund in a              rams—is a major factor responsible for the
 of the men were potent 18 months or more              nutshell, and it’s happening every day at             development and progression of the disease.
 after surgery. Walsh believes the key to suc-         Johns Hopkins. One of the best examples of            He also discovered that the major gene that
 cess here is the ability to feel the prostate         it might be called the Brady’s own “Dream             defends prostate cells against this damage,
 and surrounding territory during surgery—             Team”—a trio of investigators from different          called GSTP1 (also known as GSTp)—is
 and the expertise to interpret those findings.        scientific backgrounds—oncologist William             knocked out of commission early in the
 “It takes a great deal of experience, and also        G. Nelson, M.D., Ph.D., molecular geneticist          development of cancer. The gene, he
 tactile sensation, in determining exactly             William B. Isaacs, Ph.D., and pathologist             learned, is “hypermethylated”—in chemical
 when and where it is possible to preserve the         Angelo M. De Marzo, M.D., Ph.D.                       terms, it picks up an extra building block
 neurovascular bundle,and where it is neces-              Because prostate cancer is so very compli-         that changes its shape. This extra baggage
 sary to remove it,” he says. This is why he           cated, and its tapestry of origins seems so           has an effect that’s akin to changing a lock,
 believes that the open radical prostatectomy          intricately woven together, the goal of pin-          so the normal key doesn’t fit it any more.
 remains the “gold standard” for treatment.            pointing its earliest beginnings has long                How does this fit in with what we already
 (It’s also one of the reasons he produced the         seemed as formidable as the mountain                  know about cancer and the genes? “It’s an
 DVD of his surgery, so he could teach other           fortress in the movie, “The Guns of                   idea that’s taking on new importance,” says
 surgeons how to do this—see story, page 3.)           Navarone.” But the questions these scien-             Nelson. “In addition to helping us under-
                                                       tists are asking—and figuring out how to
                                                                           WINTER      2005      PROSTATE        CANCER         DISCOVERY              5

stand what causes cancer, methylation is also      dying, but actually, under closer inspection,        “It’s a very futuristic approach,” says
being used to help detect it, as we identify       were proliferating very rapidly. Basically,        Patrick C. Walsh, M.D., “a whole new idea
new tumor markers.” This discovery of              what De Marzo has identified is chaos on a        that we’re exploring. The idea is that a
hypermethylation changes is like finding a         microscopic level—some cells atrophic but         decreased ability to fight infections could
set of molecular fingerprints—“which means         growing out of control, some cancerous,           result in chronic inflammation, and chronic
that we have something new to look for and         some inflamed, some funny-looking, and            inflammation leads to tissue injury and ulti-
monitor, to help us detect, diagnose, and          some normal. A primordial breeding ground         mately, to oxidative damage. This, in turn,
predict the course of prostate cancer.” (For       of cancer. De Marzo named this inflamma-          leads to mutations in DNA, and mutations
more, see “Is it Cancer?” at right.)               tion PIA, for proliferative inflammatory          lead to cancer.”
   Scientists have long known that cancer is       atrophy, and identified it as a specific             One of the best examples of this is that of
caused by changes in how our genes work.           precursor lesion for prostate cancer.             stomach cancer, Walsh continues. “For years,
Tumor suppressor genes, for example, ham-             Could it be that inflammation, either in
per a gene’s ability to do its job; in contrast,   conjunction with other things, such as diet
oncogenes cause a gene’s function to be            and heredity, or—and this is the concept that
“revved up,” and result in out-of-control          has Brady scientists buzzing—by itself, is the      IS IT CANCER?
growth of cells. Methylation falls into a          cause of the oxidative damage that leads to
                                                   cancer? There is precedent for this idea.
                                                   Inflammation is known to cause damage to
                                                                                                       New Methylation
It’s chaos on a microscopic level.                 cells and to DNA; unremitting, long-term
                                                   inflammation is associated with many kinds
                                                                                                       Marker Shows
Some cells atrophic but growing                    of tumors. For example, chronic hepatitis
                                                   causes cancer of the liver; chronic stomach
out of control, some cancerous,                    inflammation, caused by a form of bacteria          The doctor suspects cancer—because a
                                                   known as h. pylori, causes stomach cancer;          man’s PSA is higher than it should be, or
some inflamed, some funny-look-
                                                   reflux esophagitis, over time, can cause            his digital rectal exam found something
ing, and some normal—a primordial                  cancer of the esophagus.                            abnormal—but the biopsy didn’t find any
                                                                                                       cancer. What happens next? Most likely,
                                                   Do Genes Hold the Answer?
breeding ground of cancer.                                                                             another biopsy—at which point, says urolo-
                                                   The next question is, what causes this              gist Mark Gonzalgo, M.D., Ph.D., as many as
                                                   inflammation? Molecular geneticist Bill             36 percent of these men will be found to
third category of genetic troublemaking,           Isaacs, Ph.D., and colleagues have been             have cancer.
causing what scientists call “epigenetic”          asking this question in an entirely different          Here’s where a new biomarker, which
change. Here, the genes aren’t altered;            way. They have spent the last decade study-         he and colleagues are working to develop,
instead, they’re silenced. A gene is methylat-     ing families with hereditary prostate cancer,       would be of great help. For one thing, Gon-
ed and boom—it’s useless. In effect, it’s put      trying to determine how mutations in cer-           zalgo notes, it could distinguish between
into a chemical straitjacket.                      tain genes stack the deck toward cancer in          cancer and BPH, benign enlargement of the
   Nelson has also learned that antioxidants       some men. They have found two genes that            prostate. “Methylation of GSTP1 has been
such as vitamin E and selenium, and crucif-        are responsible for the development of              detected in the urine and prostatic fluid of
erous vegetables such as broccoli, which pro-      prostate cancer in small clusters of families:      men with prostate cancer, but not in men
tects GSTP1, can help detoxify cells by pre-       One, located on chromosome 1, is RNASEL;            with BPH, or in normal prostate tissue.”
venting oxidative damage.                          the other, located on the short arm of chro-        Thus, instead of undergoing another biopsy
                                                   mosome 8, is called MSR1 (macrophage                and months of uncertainty, these men could
Epicenter of Cancer: Inflammation?                 scavenger receptor 1). These genes have some-       take a simple urine test. In a recent study,
Meanwhile, pathologist Angelo De Marzo,            thing very interesting in common—they’re            published in the journal Clinical Cancer
with the help of his mentor, Jonathan              both involved in the body’s defense against         Research, Gonzalgo, Christian Pavlovich,
Epstein, the Rose-Lee and Keith Reinhard           infection. When animals that lack the MSR1          and William Nelson analyzed urine speci-
Professor of Urologic Pathology, has made          gene are infected with bacteria, or animals         mens of men who underwent prostate biop-
startling findings in studies of prostate          with a defective RNASEL gene catch the              sies. They found methylation of GSTP1 in
tissue. He has seen cancer cells, and nearby,      herpes simplex virus, 60 percent of the ani-        about half of the men—in 33 percent of men
the suspicious-looking cells called PIN            mals die. And this observation, says Bill           who had negative biopsies, and in 67 per-
(prostatic intraepithelial neoplasia). PIN cells   Isaacs, “raises the intriguing possibility that     cent of men with either suspicious-looking
aren’t cancer, but they’re not normal, either;     viral or bacterial infections might be the          cells or PIN. “This suggests that there was
the general feeling among pathologists is          source of the chronic inflammation in some          hidden cancer,” says Gonzalgo, “and that
that they’re cancer waiting to happen. And         patients, and that this chronic inflammation        the biopsies had a false negative result.” He
right in the thick of these cancerous and          might be responsible for the increased risk of      believes that this test could help doctors
probably precancerous cells, he’s seen some-       prostate cancer.” If it’s true, he adds, “this      decide whether a man is at high or low risk
thing else—hotspots of inflammation. And           will profoundly affect future studies of the        for cancer, and whether he needs an early
sprinkled around this inflammation were            causes of prostate cancer, and may ultimately       repeat biopsy.
areas of atrophy—cells that appeared to be         lead to new approaches to prevent it.”
6 PROSTATE CANCER DISCOVERY                            WINTER      2005

everyone believed that stomach cancer was          What can PSA dynamics tell us?                      The records of these patients are, in effect,
caused by dietary factors, but we now know         There has got to be a better way, and Partin     a series of snapshots of cancer. Partin has
it was caused by h. pylori, which was an           and colleagues believe the key may lie in fol-   found two that are the most critical. The first
unrecognized pathogen until recently. It           lowing the dynamics of PSA—whether it            freeze-frame is the point of a man’s first rise in
would be fascinating to see whether there          comes back at all after treatment, when it       PSA after surgery. In this study, 19 percent of
might be a similar organism that causes            comes back, and how long it takes for the        the men had an elevated PSA after radical
prostate cancer.”                                  PSA levels to double. They have tracked the
                                                   course of PSA in nearly 5000 men who
                                                   underwent radical prostatectomy at the           The irony: Scientists and drug
S U R R O G AT E M A R K E R S                     Brady since 1982. Their work, which Partin
                                                                                                    companies are discovering new
Saving Years in                                    presented at the recent meeting of the Amer-
                                                   ican Urological Association, has produced        drugs “at an alarming rate.”
the Race to Test                                   enough reliably predictive data to demon-
                                                   strate that PSA can serve as a surrogate         But very few “ever make it to
New Drugs                                          marker of survival for these patients. These
                                                   findings are so impressive that the Food and     widespread use by patients,
                                                   Drug Administration (FDA) is considering
Good news for men with a rising PSA after                                                           due to lack of clinical trials.”
                                                   using them, along with data from other insti-
treatment for prostate cancer: Fresh insight
                                                   tutions, in clinical trials as surrogate mark-
into how PSA behaves, gleaned at the Brady,
                                                   ers of survival for the men who might bene-
may shorten the drug development pipeline                                                           prostatectomy; on average, the PSA began to
                                                   fit most from novel forms of chemotherapy.
by years—which means men will have access                                                           go up 8.4 years after surgery. The next freeze-
                                                      So far, the FDA has considered PSA
to new and possibly better drugs sooner                                                             frame is the point at which that number doubled.
                                                   changes too murky an endpoint for any
than ever before.                                                                                   Partin found that men with the most rapid
                                                   prostate cancer study, because there was no
   Until now, it has been difficult to study                                                        doubling time—for example, a man whose
                                                   way to tell which men with an elevated PSA
chemotherapy in men with prostate cancer                                                            PSA level goes from 1 to 2 in less than 10
because the Food and Drug Administration                                                            months—had the greatest chance of eventu-
(FDA) has historically required that the                                                            ally developing metastatic disease and dying
                                                   Partin and colleagues believe
drugs show a “survival advantage.” This                                                             from cancer. Five years after that first PSA
stipulation, although well-meaning, has            the key may lie in following the                 rise, 90 percent of the men were alive. Ten
been hard on everybody—on patients, of                                                              years after that first elevation—which means,
course, but also on drug companies, because        dynamics of PSA—whether it                       on average, 18 years after their radical prosta-
this proof can take up to 15 years.                                                                 tectomy—50 percent of those men had died.
   The irony—for men with metastatic               comes back at all after treatment,                  To put it into perspective, of these 5,000
prostate cancer, who need better medicine                                                           men, only a small percentage—2.4 percent—
to contain it, and for the scientists who are      when it comes back, and                          died of prostate cancer. But by using Partin’s
trying to get it to them—is that the drug                                                           snapshots, and identifying the men who
companies are discovering new drugs “at            how long it takes for the PSA
                                                                                                    have a rapid PSA doubling time (of less than
an alarming rate,” says urologist Alan W.                                                           10 months), Partin says, “we can identify
                                                   levels to double.
Partin, M.D., Ph.D., Bernard L. Schwartz                                                            men who might benefit from aggressive
Distinguished Professor of Urology. But                                                             therapy earlier.”
“very few of the drugs that demonstrate
                                                   after treatment are at high risk of dying,
activity against the disease in laboratory
                                                   and which men will live for years before the
testing ever make it to widespread use by
patients, due to lack of clinical trials.”
                                                   cancer progresses. As a result, treatment
                                                   groups are filled with “apples and oranges,”     Did You Participate
                                                   says Patrick C. Walsh, M.D., “and it takes
                                                   too long, for too many patients entered into     in These Studies?
                                                   a study, before a result can be determined.”
 P R O S TAT E C A N C E R D I S C O V E RY                                                         One of the nicest things about our patients
                                                      Partin and colleagues have found a way to
                                                                                                    at the Brady is their willingness to help us
 is published by The James Buchanan Brady          separate men with a rising PSA after treat-
                                                                                                    learn more—so we can do a better job of
 Urological Institute, The Johns Hopkins Medical   ment into high-risk and low-risk groups.
                                                                                                    helping them recover from prostate cancer
 Institutions, Baltimore, MD 21287-2101.           The high-risk patients tend to be a more
                                                                                                    and get on with their lives. Many of the
                                                   homogenous group, with a faster-moving
                                                                                                    readers of this publication have been gener-
                                                   form of cancer—information that can now
 Patrick C. Walsh, M.D, Professor of Urology                                                        ous partners in our process of discovery—
                                                   permit studies of drug efficacy to be carried
                                                                                                    even participating in one or more of our
 Janet Farrar Worthington, Writer/Editor           out on smaller numbers of men in a shorter
                                                                                                    studies. How have those studies turned out?
                                                   period of time.
 Claude Skelton, Designer                                                                              Earlier recovery of sexual function: This
                                                                                                    study, led by urologist J. Kellogg Parsons,
                                                                             WINTER       2005     PROSTATE        CANCER        DISCOVERY           7

M.D., asked a very simple question: Could
steroids, which have been helpful in other
                                                     study possible, thank you,” says Walsh. He
                                                     believes that if the catheter were placed         In Relentless
types of neurological injury, help men
recover sexual function after radical prosta-
                                                     more superficially in the subcutaneous tis-
                                                     sue, rather than on top of the muscles, it        Pursuit of the
tectomy? The 70 men in this study received
either a short course of high-dose steroids,
                                                     might prove more helpful.
                                                        Who needs a transfusion after surgery? A bit   “Smart Bomb”
or a placebo immediately after surgery. The          of background before we tell this story: The
                                                                                                       In many ways, it’s the ultimate weapon—
good news is that the steroids did not cause         main deciding factor on who needs a trans-
                                                                                                       cancer-killers delivered at the molecular
any side effects; however, they didn’t               fusion is the concentration of red blood
                                                                                                       level, targeting only cancer cells, leaving the
improve the recovery of sexual function,
                                                                                                       rest of the body unscathed. Gene therapy
either. One year later, 74 percent of the men
                                                                                                       in the laboratory has been remarkably
on steroids, compared to 71 percent of the          “This is an important study,                       successful, giving scientists a glimpse at
men on placebo, were potent. These results
                                                                                                       what could be. Gene therapy in humans,
are not significantly different. However, they       because it may result in fewer
                                                                                                       however, has turned out to be something of
do confirm earlier Brady studies that show
                                                     patients requiring transfusions.”                 a different animal. The basic concept is to
excellent recovery of sexual function at one
                                                                                                       sneak new genes into cancer cells that will
year. In earlier studies, 70 to 75 percent of
                                                                                                       stop or disrupt their growth, or to use a
men were potent at one year, and by 18
                                                                                                       specific genetic marker inside a cancer cell
months, 86 to 90 percent were potent. The            cells in the blood, and there are two ways to
                                                                                                       to trigger a “smart bomb.”
results also confirm the excellent recovery of       determine this. One is the hematocrit, the
                                                                                                           When the cancer-killing bomb is delivered
urinary control shown in earlier studies. At         percentage of red blood cells in the blood;
                                                                                                       in the form of a virus—viruses are attractive
one year after surgery, 96 to 100 percent            the normal hematocrit is about 45 percent.
                                                                                                       drug-delivery systems, because their one goal
were wearing no pads.                                The other critical measurement is the
                                                                                                       is to replicate like mad—the drug has had
   For pain after surgery, continuous local anes-    amount of hemoglobin in the blood.
                                                                                                       to contend with the body’s own immune
thetic: In this study, a small catheter was          Hemoglobin is the major component of
                                                                                                       system, which (as it’s supposed to do) recog-
placed in the incision after radical prostatec-      red blood cells, and the normal level is
                                                                                                       nizes it as an invader, and starts attacking it.
tomy. The catheter, which was left in place          around 15 grams per deciliter (g/dl). It is
                                                                                                       Thus, from the moment it hits the blood-
for three days, was attached to an elastic           well known that if a man’s hemoglobin
                                                                                                       stream, the cancer drug-carrying virus—in
                                                     falls lower than 6 to 8 g/dl, he has a higher
                                                                                                       effect, a Trojan horse—is racing the clock,
                                                     risk of having a heart attack. Traditionally,
“Somewhat to our surprise, we                        then, this has been the primary trigger
                                                     point for transfusions. However, because
 learned that men with higher                                                                          “We can time the bombs to go off
                                                     that hemoglobin count is only half of nor-
                                                     mal, doctors have worried that men who are         all at once, unleashing a tidal
 hemoglobin levels did not appear                    anemic at this level might have greater
                                                     fatigue, and take longer to recover from sur-      wave—instead of several large
 to recover faster, have less fatigue,
                                                     gery. Thus, Brady surgeons have traditional-
 or improved aerobic capacity.”                      ly used a hemoglobin cutoff of 10 g/dl as          splashes—of cancer cell death.”
                                                     the trigger point for giving patients back
                                                     their own blood.
                                                                                                       trying to get to the cancer before the body’s
pump that dispensed either a local anes-                In a recent study, 184 men were randomly
                                                                                                       immune system gets to it, and begins creat-
thetic (0.5 percent bupivacaine) or a harm-          chosen to receive transfusions either when
                                                                                                       ing antibodies. Also, altered viruses haven’t
less saline solution. (The study was “double-        their hemoglobin was less than 7.5 g/dl, or
                                                                                                       proven as lethal as the scientists who doc-
blind,” which means neither doctors nor              less than 10 g/dl. The men completed quality-
                                                                                                       tored them had hoped. Because a virus
patients knew which man was receiving the            of-life questionnaires after surgery. “Some-
                                                                                                       simply exists to replicate—like kudzu in the
placebo.) One hundred men were random-               what to our surprise, we learned that men
                                                                                                       South—killing cells is its byproduct, not its
ized to receive either the local anesthetic          with higher hemoglobin levels did not
                                                                                                       number one job.
or the placebo. “It was a great idea,” says          appear to recover faster, have less fatigue, or
                                                                                                          These are some of the challenges facing
Patrick C. Walsh, M.D. “Wouldn’t it be won-          improved aerobic capacity,” comments
                                                                                                       Ron Rodriguez, M.D., Ph.D., assistant pro-
derful if it were possible to give local anes-       Walsh. “This is an important study, because
                                                                                                       fessor of urology, medical oncology, and
thesia directly to the wound, and avoid the          it may result in fewer patients requiring
                                                                                                       cellular and molecular medicine. Lesser
side effects of intravenous and oral nar-            transfusions.” These results also may reduce
                                                                                                       scientists might give up; Rodriguez, instead,
cotics?” Unfortunately, he adds, “that is not        the need for men to donate blood before
                                                                                                       digs in his heels, doubles and redoubles his
the way it worked out.” The men who                  surgery. “In this modern era of surgery, with
                                                                                                       efforts, and finds new ways around the
received the anesthetic did not need fewer           our current understanding of the anatomy,
narcotics for pain relief, and their pain            only a small number of men would require a
                                                                                                          Rodriguez has figured out a means of
scores did not show any significant improve-         blood transfusion if the trigger point were
                                                                                                       genetically altering these genes to make them
ment. “To all of the men who made this               set at 7.5 g/dl.”
8 PROSTATE CANCER DISCOVERY                           WINTER       2005

more potent, and has engineered the ability                                                          Biomarkers to the Rescue
to switch them on and off by giving specific                                                         Instead, say Carter and Chan, what’s needed
medications. One drug, bicalutamide, turns                                                           are new biomarkers—new ways to detect
the gene on, and geldanomycin turns it off.                                                          cancer earlier, and determine the need for
This way, he says, “we can time the bombs                                                            biopsy. “A biomarker,” explains Robert Veltri,
to go off all at once, unleashing a tidal                                                            Ph.D., associate professor of urology, “is a
wave—instead of several large splashes—of                                                            cancer property that can be objectively meas-
cancer cell death.”                                                                                  ured, and used to monitor someone’s disease.
   Rodriguez has also developed a series of                                                          It can also tell us how well a particular therapy
tiny proteins that specifically target and                                                           is working.” Veltri, Chan, and several Brady
attach themselves to the prostate-specific                                                           scientists are exploring many promising new
membrane antigen (PMSA), the outer husk                                                              biomarkers, not only as means of improving
of the prostate cancer cell. By tucking these                                                        diagnosis, but of predicting a man’s stage of
tiny proteins into the viruses, he will be able                                                      cancer and his risk of recurrence, and of
to deliver them intravenously—“which                                                                 sounding the earliest possible alarm that can-
means we can target cancer cells throughout                                                          cer has spread, so that it can be treated while
the body.”                                                                                           the disease is most vulnerable.
   Rodriguez and colleagues also are explor-                                                             Chan and colleagues are using a sophisti-
ing other delivery systems. Among the most                                                           cated computerized proteomic technology—
promising are liposomes. The body doesn’t         Carter: PSA doesn’t always tell the whole story—
                                                  so finding one PSA level that’s “normal” for       minuscule chips of protein, added to just
make antibodies to liposomes, little bubbles                                                         one drop of a man’s blood. The protein chip
of fat that coat DNA. Think of two soap           every man is impossible.
                                                                                                     acts like a tiny magnet, attracting all the
bubbles meeting and sticking together—                                                               proteins in that blood drop to stick to its
that’s how a liposome dissolves through a                                                            surface. This process is a bit like dangling a
cell’s fatty membrane, and that’s how             the last decade studying PSA and figuring          hook into the water, and seeing what bites.
Rodriguez may be able to bypass the body’s        out how best to use it to diagnose and mon-        In this case, Chan is fishing for proteins. A
best efforts to fight off even more effective,    itor prostate cancer—discussed the dilemma         sophisticated computer technology called
cancer-killing medications.                       of low PSA levels and prostate cancer. In the      Mass Spectrometry allows Chan to see what
   “Progress in gene therapy is slow in com-      recent Prostate Cancer Prevention Trial, he
ing, but it’s being made,” says Patrick C.        noted, a small number—2 percent—of a
Walsh, M.D..“I’m thankful we have someone         group of nearly 3,000 men with PSA levels          The protein chip acts like a tiny
like Ron who is working diligently toward         below 4 turned out to have serious, high-
this important end.”                              grade disease.                                     magnet, attracting all the pro-
   This work was funded in part by Donna             However, Carter doesn’t believe a lower
and Robert Tompkins.                              PSA cutoff will solve the problem. One rea-        teins in the blood drop to stick
                                                  son, he says, is that PSA doesn’t always tell
                                                  the whole story—so finding one PSA level           to its surface. It’s a bit like
                                                  that’s “normal” for every man is impossible.
When the PSA Test                                 “High-grade cancers actually produce less
                                                  PSA per gram of tissue than low-grade
                                                                                                     dangling a hook into the water,

Can’t Do It All                                   cancers.” For this reason, even though high-
                                                  er-grade cancers are often larger in volume
                                                                                                     and seeing what bites.

New Biomarkers To Fill in                         than low-grade cancers, the PSA level does         he caught; each protein has its own charac-
                                                  not accurately indicate the volume of the
the Gaps                                          cancer.
                                                                                                     teristic “signature” of peaks and valleys. It
                                                                                                     also shows Chan what he didn’t catch—any
Low PSA—anything under 4.0—is good,                  Also, as many as 75 percent of men with a       proteins that are missing, or mangled, or
right? The answer is, most of the time, but       PSA higher than 4 who get a biopsy turn            changed, are of interest, as well.
not always. And this prompts the next             out to have BPH, notes Daniel W. Chan,                Chan’s next job is to filter out the back-
question: Would a lower PSA cutoff find           Ph.D., professor of pathology, oncology,           ground noise, to find the real molecular
more cancer? Yes, undoubtedly. But not all        urology, and radiology. “PSA is by no means        signature of cancer—which may be different
of these cancers would need to be treated,        perfect,” he concurs. Even with more sophis-       in each man, because prostate cancer itself is
and some men with insignificant, slow-            ticated PSA tests—of free or complex PSA—          so complex, and made up of so many differ-
growing disease would wind up getting             “it gives us some help in deciding who needs       ent types of cells and genetic configurations.
prostate biopsies they don’t need.                a repeat biopsy. However, with free PSA, less      “We want to decide which of these peaks are
   And yet, some of these cancers are high-       than 10 percent is considered high-risk, and       real proteins, and which have clinical value
grade (with a Gleason score of 7 to 9), and       greater than 25 percent is considered low-         in terms of early detection of prostate can-
potentially deadly. In an editorial in the        risk. What happens if your free PSA is             cer.” He and colleagues at Hopkins have
New England Journal of Medicine, urologist        between 10 and 25 percent? This is another         developed a set of “bio-informatic” tools—
H. Ballentine Carter, M.D.—who has spent          diagnostic gray zone.”
                                                                           WINTER       2005      PROSTATE        CANCER        DISCOVERY           9

“High-grade cancers actually                       urology, “they sustain some sort of damage,        neuroimmunophilin compound called GPI
                                                   at least temporarily.”                             1485, taken in pill form by men after radical
 produce less PSA per gram of                         The reasons for this damage—and the             prostatectomy. The Brady Urological Insti-
                                                   specific nature of the nerve injury—remain         tute is one of 13 medical centers in the Unit-
 tissue than low-grade cancers.”                   unclear, but the result for many men is a          ed States taking part in this clinical trial,
                                                   frustrating delay in the recovery of potency,      sponsored by Guilford Pharmaceuticals, Inc.
                                                   the ability to have and maintain an erection.      Men will be randomly assigned either to the
 new ways to analyze all of this information.
                                                   In breakthrough work with Hopkins neuro-           drug, or to a placebo; all of the men are
 When he finds likely-looking proteins, he
                                                   scientist Solomon Snyder, M.D., several years      required to record their impressions about
 purifies them, sequences them, and deter-
                                                   ago, Burnett discovered that rats with nerve       their functional recovery.
 mines their molecular fingerprint. Because
                                                   injury and erectile dysfunction (similar to that      “We hope to be able to report the results
 prostate cancer is so variable from man to
                                                                                                      from the study within the next year,” says
 man, Chan isn’t looking for one key suspect,
                                                                                                      Burnett. “So far, we know that the men have
 but a whole gang of them—a panel, or a            The rats treated with an                           tolerated the drug well, with no major side
 multiplex, of biomarkers. He then wants to
                                                                                                      effects. Any evidence that the drug therapy is
 test these biomarkers in as many patients as      immunophilin ligand—a “jump-                       effective in enhancing the recovery of erectile
 possible, on patients at Hopkins and centers
                                                                                                      function after radical prostatectomy will
 worldwide. He also believes this technology       starter” that activates these
                                                                                                      serve as an important advance in the field,
 will produce new tests that can help diag-
                                                   proteins—showed dramatically                       and may also help us develop further neuro-
 nose early recurrence of cancer.
                                                                                                      protective interventions in the future.”
                                                   less nerve damage, and much
Some biomarkers under study include:
• Prostate-breast overexpressed gene-1             greater restoration of function.
  (PBOV1): Veltri and colleagues discovered
  that this gene is, as its name suggests,         They had stronger erections,
                                                                                                      Does Sexual Activity
  overproduced in prostate and breast
  cancers. He is working to develop a new          and recovered earlier.                             Affect My Risk
  blood and biopsy test that can help deter-
  mine if cancer is present, and whether it
                                                                                                      of Cancer?
                                                   found in men after radical prostatectomy)
  is likely to need treatment.                                                                        What does sex have to do with prostate can-
                                                   were helped greatly by the use of a solution
• GSTP1: Veltri and Partin are evaluating a                                                           cer? Could a man’s sexual activity have any
                                                   containing immunophilins. Immunophilins
  test to measure GSTP1, which helps the                                                              repercussions—one way or the other—on his
                                                   are special healing proteins made by nerve
  body fight oxidative damage to DNA in                                                               risk of getting prostate cancer?
                                                   tissue; when a nerve is injured, they rush to
  cells. This test may be useful for men who                                                             In the past, scientists considering this
                                                   its aid, and help repair the damage. The rats
  have what appears to be prostate cancer,                                                            question have come up with good but
                                                   treated with an immunophilin ligand—a
  based on a rectal exam, but cancer-free                                                             conflicting theories, says epidemiologist
                                                   “jump-starter” that activates these proteins—
  biopsies.                                                                                           Elizabeth A. Platz, Sc.D. Some researchers
                                                   showed dramatically less nerve damage, and
• NMP44: Partin and Chan are working on                                                               speculate that men who have sex more often
                                                   much greater restoration of function. They
  a test to detect NMP44, a protein that                                                              “may be more likely to acquire a sexually
                                                   had stronger erections, and recovered earlier.
  binds with Vitamin D.                                                                               transmitted disease, which may infect the
                                                   This and other immunophilin ligands, Bur-
                                                   nett says, work by stimulating receptors in        prostate, cause inflammation and other
                                                   nerve tissue “which, in turn, promote healing      damage, and increase the risk of prostate

 Protecting the                                    and recovery in injured nerves.”
                                                       Burnett’s first immunophilin solution
                                                                                                      cancer.” (For more on the growing link
                                                                                                      between inflammation and prostate cancer,

 Nerves, Restoring                                 was a ligand called FK506, a drug commonly
                                                   used to suppress the immune system in peo-
                                                                                                      see story on page 4) Another thought is that
                                                                                                      men who have sex more often have a higher

 Potency Sooner                                    ple who have undergone organ transplants.
                                                   He and colleagues have since developed even
                                                                                                      sex drive, because of a higher level of male
                                                                                                      hormones—which, in turn, may increase the
                                                   more targeted ligands that don’t affect the        risk of prostate cancer.
 Just as a knight heading off to battle needs
                                                   immune system, and are just as successful in          But other researchers believe that sexual
 armor, or a child needs a sweater on a cold
                                                   soothing, protecting, and invigorating these       activity may actually decrease the risk of
 day, nerves sometimes need extra protection,
                                                   delicate nerves.                                   prostate cancer—that regular ejaculation, if
 too. This is especially true in the case of the
                                                       Now, in what Burnett calls an example          you will, “cleans house” in the prostate, mak-
 fragile nerves involved in erection in men
                                                   of “true translational research,” a medical        ing it a less welcome harbor for cancer-caus-
 who undergo radical prostatectomy. No
                                                   therapy that originated in the laboratory has      ing agents, infection, and stagnant materials
 matter how meticulous the surgeon, the
                                                   been developed for a clinical investigation        that could lead to inflammation.
 trauma of surgery—any surgery—is hard on
                                                   that’s currently under way. A new study—the           Previous studies have been inconclusive,
 the nearby nerves. Even in the best of cases,
                                                   first of its kind—will test this therapy, a        notes Platz, but “taken together, they hint
 says Arthur L. Burnett, M.D., professor of
1 0 PROSTATE CANCER DISCOVERY                          WINTER      2005

that men who have more sex, or who have
had a sexually transmitted disease, are more     Study Raises                                                                 prednisone and
                                                                                                                              Taxotere every three
likely to have prostate cancer.”
   Platz and her colleagues at Harvard and       New Hope for                                                                 weeks. Side effects,
                                                                                                                              including a decrease
the National Cancer Institute were uncon-
vinced. As part of a massive study, led by       Chemotherapy                                                                 in white blood cells,
                                                                                                                              were moderate and
epidemiologist Michael Leitzmann at                                                                                           reversible. “In gener-
                                                 At last, definitive news: Chemotherapy pro-
Harvard, they recently studied nearly 30,000                                                                                  al, treatment was
                                                 longs life in men with prostate cancer—and it
men participating in the Health Profes-                                                                                       well tolerated,” says
                                                 may be most effective when it is started early,
sionals Follow-up Study. Most of these men                                                                                    Eisenberger. “Men
                                                 and used aggressively. This is the word from a    Mario Eisenberger
were white and middle-aged, and very few                                                                                      receiving Taxotere
                                                 massive, worldwide study of 1006 men with
had ever had a sexually transmitted disease.                                                       also were more likely to have a drop in their
                                                 hormone-refractory cancer, led by Mario
“In 1992, we asked the men who did not                                                             PSA level, better control of pain, and
                                                 Eisenberger, M.D., the R. Dale Hughes Profes-
have prostate cancer to report their typical                                                       improvement in quality of life.”
                                                 sor of Oncology and Urology, published in
number of ejaculations per month in their                                                             Because of the study’s results, the Food
                                                 the New England Journal of Medicine.
                                                                                                   and Drug Administration has approved the
                                                    The results come after years of clinical
                                                                                                   use of Taxotere for prostate cancer, says
Could a man’s sexual activity                    trials, of dozens of chemotherapy com-
                                                                                                   Eisenberger, who presented these findings at
                                                 pounds and drug regimens—many of them
                                                                                                   the plenary session of the American Society
have any repercussions—one way                   developed at the Kimmel Cancer Center by
                                                                                                   of Clinical Oncology. “This important study
                                                 Eisenberger and colleagues. Over the last
                                                                                                   sets a new standard for chemotherapy in
or the other—on his risk of                      decade, Eisenberger and colleagues have
                                                                                                   prostate cancer,” he says. “It also indicates
                                                 pioneered a new approach to chemotherapy,
getting prostate cancer?                                                                           that prostate cancer is a tumor that is as
                                                 hitting prostate cancer increasingly harder
                                                                                                   sensitive to chemotherapy as other tumor
                                                 and earlier—when it is much more vulnera-
                                                                                                   types, such as breast cancer.” Finally, he adds,
                                                 ble—and also using “smart” drugs to target
twenties, forties, and during the past year,”                                                      the results point to further trials aimed at
                                                 specific molecular steps of cancer cell growth.
says Platz. Over the next eight years, nearly                                                      men with less advanced disease—for example,
                                                 The journey to this point has been hard,
1,500 of these men went on to develop                                                              men after radical prostatectomy, whose
                                                 often discouraging, and yet Eisenberger
prostate cancer.                                                                                   pathology suggests that some cancer is still
                                                 has always believed that the secret code of
   The scientists found that men who report-                                                       present, or men with no symptoms but rapid
ed more ejaculations—more than 21 a month,                                                         PSA doubling times (see related story on
on average across their adult life—had two-      This shows that “prostate cancer                  page 6). “Our clinical trials should now shift
thirds the lifetime risk of prostate cancer of                                                     to using it even earlier, to delay or prevent
men who reported fewer (4 to 7) ejaculations     is as sensitive to chemotherapy                   the onset of cancer-related symptoms, and to
a month. Notes Platz: “Compared with men                                                           further prolong survival.”
reporting fewer ejaculations per month at all    as other tumor types, such as
ages, men who reported 21 or ejaculations
per month had one-fourth the risk of             breast cancer.”
prostate cancer.”
   Certain important features of this study
make these observations more credible,
                                                 cancer was crackable—that it is just a ques-
                                                 tion of finding the right molecular key, or
she adds. One is the sheer number of men
involved; another is “the fact that the men
                                                 set of keys, and knowing the right lock, or
                                                 bank of locks.
                                                                                                   New Head of
reported their ejaculation frequency well
before they were diagnosed with prostate
                                                    This 24-country trial is the largest study
                                                 ever conducted in men with hormone-refrac-
                                                                                                   Radiation Oncology
cancer.” Also, the scientists were able to
                                                 tory prostate cancer—men with cancer that         Imagine looking at something—say, a gar-
rule out such factors as a man’s history of
                                                 has spread after months or years of hormonal      den—through two different lenses. One lens
sexually transmitted diseases, which could
                                                 therapy. It was chaired by Eisenberger, along     zooms in so much that you can focus on a
have clouded the results.
                                                 with physicians Ian Tannock, from Canada,         single weed; the other gives you an aerial
   Another recent study of many men, with
                                                 and Ronald DeWit, from the Netherlands.           shot. This is how Theodore L. DeWeese,
and without prostate cancer, has produced
                                                 In the landmark study, men were randomly          M.D., works on prostate cancer. He deals
similar findings, says Platz. “Based on these
                                                 assigned to receive a combination of pred-        with the very small—cancer on a molecular
two large, well-conducted studies, men
                                                 nisone and docetaxel (Taxotere) a drug in the     level, in viral gene therapy studies with urol-
should not be worried that frequent ejacula-
                                                 taxol family, used to treat breast cancer—        ogist Ron Rodriguez, and work on oxidative
tion will cause prostate cancer.” The next
                                                 given weekly, or given every three weeks, or      damage with oncologist Bill Nelson—and the
step, she adds, is to figure out why frequent
                                                 to receive a conventional drug regimen of         bigger picture—pulling together teams of
ejaculation seems to have this protective
                                                 mitoxantrone and prednisone. The men who          physicians and scientists, tailoring specific
effect, and the role inflammation plays here.
                                                 showed the biggest improvement received           therapy for individual patients, and working
                                                                        WINTER       2005      PROSTATE        CANCER        DISCOVERY           11

 with surgeons and oncologists to design new
 treatment combinations.
                                                                            with lung cancer.”
                                                                            Song will also lead      Laparoscopic Radical
    DeWeese is recognized internationally
 for his expertise in the molecular aspects of
                                                                            the prostate cancer
                                                                            clinical research        Prostatectomy:
 radiation’s interaction with human cells,
 particularly prostate cancer cells. He also
                                                                               DeWeese is creat-     Less is More
 has designed systems to deliver droplets of                                ing a new division
                                                                                                     In the world of surgery, laparoscopic radical
 cancer-killing viruses—highly precise com-                                 of medical physics,
                                                                                                     prostatectomy—removing the prostate
 puter programs that place tiny doses of                                    bringing in Ph.D.
                                                                                                     through tiny keyholes, instead of a larger
 virus or radiation at exact intervals within                               scientists who can
                                                  Ted DeWeese                                        incision—is the “new kid on the block,” but
 the prostate, guided by transrectal ultra-                                 apply physics and
                                                                                                     its results are exciting.
 sound and CT imaging. But at Hopkins, he         mathematics expertise to a host of ques-
                                                                                                        Over the last three years, urologists
 is also renowned for his ability to make         tions. For example: “What does it mean for
                                                                                                     Li-Ming Su, M.D., and Christian Pavlovich,
 multidisciplinary collaborations work—so         the patient when a specific gene is function-
                                                                                                     M.D., at the Johns Hopkins Bayview Medical
 much so, that he has been named the first        al or not functional, and how can this help
                                                                                                     Center, have performed more than 330 of
                                                  us design a better radiation strategy? We
                                                                                                     these laparoscopic procedures. Comparing
                                                  tend to treat everybody the same,” says
                                                                                                     their results with those for the “gold stan-
“We will be nearly doubling our                   DeWeese. “But if you could genetically ‘type’
                                                                                                     dard” procedure, the nerve-sparing radical
                                                  a man with prostate cancer, you could indi-
 faculty—from 12 to 23—over                                                                          prostatectomy, the surgeons have found that
                                                  vidualize that man’s therapy far more than
                                                                                                     their patients need less pain medication after
                                                  we do today.”
 the next three years, and tripling                                                                  surgery, and have a shorter convalescence—
                                                     DeWeese hopes to be able to generate an
                                                                                                     four weeks, instead of six weeks. In a review
                                                  instantaneous report card that tells him how
 our lab space.”
                                                  well radiation is working in a patient, “in a
                                                  real-time fashion, what this is doing to the       Patients need less pain
 director of the new Department of Radia-         tumor. But almost as importantly, can we
 tion Oncology and Molecular Radiation            also monitor the normal tissues that happen        medication after laparoscopic
 Sciences. He is a bridge-builder: Leader of a    to be getting radiation also? Which patients’
 National Cancer Institute Specialized            rectums are more sensitive than others’? If        surgery, and have a shorter
 Program of Research Excellence (SPORE)           the normal tissue is not being affected, we
 “translational science” project—turning          could give more radiation. If it is being          convalescence—four weeks,
 ideas developed in the laboratory into           harmed, we could cut back, or come up with
 new forms of treatment for patients, and         another approach.”                                 instead of six weeks.
 leader of a Department of Defense Cancer            With the goal of nearly instantaneous
 Consortium grant project in adenoviral gene      feedback from a PET or other nuclear
                                                                                                     of the first 200 laparoscopic radical prostate-
 therapy (working with Rodriguez, whose           medicine scan, DeWeese and colleagues are
                                                                                                     ctomy procedures performed at Hopkins,
 work is discussed on page 7).                    testing molecular markers, and working to
                                                                                                     Su and Pavlovich found that 70 percent of
     “The treatment of prostate cancer has        develop them into a clinical trial—which
                                                                                                     their patients recovered full urinary control
 evolved, so that no one specialty has ‘owner-    would be the first of its kind.
                                                                                                     at six months, 90 percent were continent at
 ship’ of it any more,” says Patrick C. Walsh,       In other research, DeWeese and colleagues
                                                                                                     one year; and only a very small percentage
 M.D.. “Because the disease comes in so many      are studying how cells recover from radia-
                                                                                                     (0.6 percent) of men experienced a bladder
 different forms, there will never be a single    tion damage. “We don’t want a cancer cell
                                                                                                     neck contracture (a treatable condition)—
 standard way to beat it; we need many            to repair damage; we want to kill it,” he
                                                                                                     scar tissue that can impede urine flow.
 options, and many scientific minds from dif-     explains. Cells have specific sensors that
                                                                                                        What about cancer cure? Early results,
 ferent disciplines turned to the problem. Ted    sound the alarm that there has been dam-
                                                                                                     again, are very encouraging, says Su. With
 exemplifies this team approach beautifully.      age, and call for genetic repair crews. “Those
                                                                                                     an average follow-up time of one year, “98
 Both Hopkins and our patients are very           sensors are like the cell’s radar,” he says.
                                                                                                     percent of our patients have shown no
 lucky to have him as our leader.”                “They constantly scan the cell. If it’s injured,
                                                                                                     recurrence of PSA.”
    DeWeese is excited about the possibilities    the sensor sees it, and starts a whole cascade
                                                                                                        And potency after surgery? The surgeons
 of his new job, he says. “We will be nearly      of events to repair the damage.” If those sen-
                                                                                                     have worked to modify their procedure to
 doubling our faculty—from 12 to 23—over the      sors can be disabled—and this can happen,
                                                                                                     preserve the nerves responsible for erection.
 next three years, and tripling our lab space.”   DeWeese found out, by preventing a certain
                                                                                                     “Our goal is to replicate the meticulous
 One of those new faculty members is radia-       protein from being made—then the damage
                                                                                                     dissection achieved during open surgery, in
 tion oncologist Danny Y. Song, M.D., who         doesn’t get reported. And this means that
                                                                                                     the anatomic nerve-sparing radical prostate-
 will “re-establish and lead our prostate         radiation and chemotherapy can kill more
                                                                                                     ctomy,” says Su. He and Pavlovich use fine
 brachytherapy effort as well as participate      cancer cells at lower doses.
                                                                                                     dissecting instruments to ease the fragile
 in the management of other patients with
                                                                                                     nerves from the prostate surface as gently
 genitourinary malignancies, and patients
1 2 PROSTATE CANCER DISCOVERY                           WINTER      2005

as possible. Also, the surgeons avoid using                                                                        Karhadkar, Berman, and Beachy
any electrical or heat energy, such as cautery,                                                                    have linked Hedgehog activity
during their dissection of the nerves. This                                                                        to prostate cancer’s wanderlust.
is because animal studies, done by Su and                                                                          The cancer can spread only if the
colleagues, have suggested that these energy                                                                       pathway goes with it.
sources produce a dramatic and immediate
detrimental effect on nerve function. “By
incorporating these concepts into our nerve-
sparing laparoscopic procedure, we’ve been
able to achieve short-term potency results                                                                           with cancer’s wanderlust—
similar to that of open surgery,” says Su. He                                                                        this suggest that the cancer
adds that in men who were potent before                                                                              can spread only if the path-
surgery and who had both nerve bundles                                                                               way goes with it.
spared, 55 percent reported having success-                                                                             “Think of the soil and
ful intercourse at 6 months and 75 percent                                                                           seeds,” explains Patrick C.
at 12 months. However, they were only able                                                                           Walsh, M.D. “The soil is the
to spare both nerve bundles in about half of      was mutated in fruit flies, the insects were      stroma of the prostate, and the cancer cells
the patients. “We are continuing to refine        born with telltale, hedgehog-like prickles).      are the seeds. If these cells spread but lack
our techniques to make it possible to save           In breakthrough research, published in         the proper soil, they can’t survive. But if
both neurovascular bundles more often,”           the journal Nature, Hopkins scientists have       they can manufacture the Hedgehog pro-
says Su.                                          shown that the Hedgehog pathway is the            tein, they can make the soil that they need—
                                                  key to metastasis—as essential for a cancer       they can pack their lunch and take it with
                                                  cell to live outside its home-base environ-       them.”
                                                  ment as oxygen is to a deep-sea diver. Even          The next part of the story involves one-
K E Y T O M E TA S TA S I S                       more exciting—these scientists have proven        eyed sheep. In the 1950s and 1960s, several
                                                  that they can block the pathway, and stop         generations of sheep in the western United
The Hedgehog                                      metastasis in its tracks.
                                                     The implications of this work are far-
Pathway                                           reaching. “If we can use Hedgehog activity        “Manipulating the Hedgehog
                                                  to predict whether a tumor will metastasize,
It is the great mystery of prostate cancer:       we will have a great diagnostic tool, and we       signaling pathway may also offer
Like people, some cancer cells are better         are testing this hypothesis,” says David
than others, and some are far worse. Some         Berman, M.D., Ph.D., assistant professor           a completely new way to treat
cancer cells don’t seem to do much; others        of pathology, urology and oncology. But
quickly become dangerous, spread to sites                                                            metastatic prostate cancer.”
                                                  Berman and colleagues Sunil Kahadkar,
far away from the original tumor, and even-       M.D., and Philip Beachy, Ph.D., professor
tually, if unchecked, ravage the body. Scien-     of molecular biology and genetics and a           States were born with only one eye—Cyclops
tists have long sought to understand the          Howard Hughes Medical Institute investiga-        sheep. Their birth defect turned out to be
                                                  tor, are aiming higher. “Manipulating the         caused by something their mothers were
                                                  Hedgehog signaling pathway may also offer         grazing on—a plant that was shown to
The Hedgehog pathway is as                        a completely new way to treat metastatic          contain a chemical called, appropriately,
                                                  prostate cancer,” Berman says.                    cyclopamine. When Beachy knocked out the
essential for cancer to live outside
                                                     The pathway is not present in normal           gene that makes the Hedgehog protein in
its home-base environment as                      prostate cells, nor in most low- to middle-       mice, they produced “Cyclops”offspring, as
                                                  grade prostate cancer cells. But it’s very        well. From this observation, he deduced and
oxygen is to a deep-sea diver.                    active in metastatic deposits; it’s also active   then demonstrated that cyclopamine must
                                                  in cancer cells of men who were thought to        block the Hedgehog pathway.
                                                  have localized prostate cancer, but who later        In laboratory experiments on mice with
difference between indolent and overzealous       developed metastases.                             aggressive prostate tumors, from cell lines
prostate cancer cells. What gives some cells         The investigators looked for detectable        established by Brady scientist John Isaacs,
the power to slip away and cause trouble?         activity of the Hedgehog signaling pathway        Ph.D., Kahadkar blocked the Hedgehog
   Now, they think they’ve found at least         in prostate specimens from men with local-        signal with daily injections of cyclopamine.
one answer. The secret seems to be a com-         ized disease, and from men who died of            Cyclopamine slowed or reversed the cancer’s
mon protein pathway, normally responsible         metastatic cancer. They found Hedgehog            growth, and prolonged the animals’ lives.
for embryonic development of the lung,            activity in only three of 12 localized tumors—       “It’s unbelievable,” says Walsh. “This
pancreas, prostate, part of the brain, and        but in every one of the metastatic cancers,       work shows a whole new approach to treat-
many other organs. The protein in question        and at levels that were 10 to 100 times higher.   ing advanced prostate cancer—take away the
is called the Hedgehog protein (years ago,        In effect, they equated Hedgehog activity         soil, and the cells die.”
scientists discovered that when this protein
                                                                              WINTER       2005     PROSTATE         CANCER       DISCOVERY          13


The Patrick C. Walsh Prostate Cancer Research                     Barbara K. & Donald H.         Nestor T. Carbonell          William K. Davenport
Fund was created to ensure that a multidisciplinary                 Bernstein                    John T. Carey                Lynn R. & Harold Davidov
approach to discovery in the field of prostate cancer             James O. Berry                 Elizabeth P. & Peter E.      Kenneth D. Davis
                                                                  Kenneth Bickerton                 Carlson                   Robert W. Deagan
flourishes at the Johns Hopkins Medical Institutions.             Robert G. Bigham               Michelle & Charles S.        Mr. & Mrs. Michel De
The generosity of those listed makes groundbreaking               Joan M. & Mark Bilodeau           Carlton                      Beaumont
research possible and supports the best and brightest             Richard N. Binetsky            Paul J. Carroll              Gloria & John M. Decaro
minds working to eradicate prostate cancer.                       Dr. & Mrs. Peter S. Bing † ▲   Lacena R. & Benjamin S.      The Deeks Family
                                                                  A. William Blake Jr.              Carson Sr.                   Foundation†
This list recognizes donors to The Patrick C. Walsh               Ronald A. Blanken              Elva E. Carty                Robert D. Delay
Prostate Cancer Research Fund from April 1, 2002 to               William F. Blue                Thomas J. Casey              Chad Demarest
                                                                  Peter E. Blum                  Sara Castro-Klaren & Peter   Lynda Demarsh-Mathues
October 30, 2004.                                                 Matthew Bocchino                  Klaren                    Dominick Denaples
We are especially grateful to the Brady Advisory Council          Mr.* & Mrs. Louis J.           Aliye D. Caycik & George     Stephen C. Dennett
                                                                    Boland                          Ozturk                    Jane & Jeremiah Denton Jr.
for their vision and dedicated support which made this            Louis J. Boland Jr.            Albert Celeste               William M. dePasquale
fund possible.                                                    Ivor Boofty                    Jennifer A. Chalsty † ▲      Robert S. DeWaters Jr.
                                                                  Ronald Book                    John S. Chalsty † ▲          Gurmeet S. Dhillon
                                                                  Edgar Boone                    William E. Chapman           George DiCenzo
Anonymous (45)                     Dorsey N. Baldwin              Melinda F. Booth               Loris J. Charchian           Sallie Dichter
Steven B. Aaronson                 H. Furlong Baldwin             Peter B. Booth                 Kathleen O. & James Cirbus   E. Kearney Dietz
Sharon & Domenico                  Robert F. Ballard              Jo N. Booze                    Alice B. & A. James Clark    Russell Distler
   Abitino                         Michael Ballo                  Herbert Borger                 Patrick L. Clark             Mr. & Mrs. Otto B. DiVosta
Abramson Foundation                Sir Anthony & Lady             Adele & Samuel Borger          Robert E. Clayton            Paul Dixon
Sandra W. & Rabbi David              Bamford                      Emanuel Borok                  F. Pete Clements             W. Boulton Dixon
   L. Abramson                     Halim I. Barakat               David H. Boshart               Benjamin Coates              Arthur Dole
Jessica J. & Samuel J.             Milton H. Barbarosh            Elaine & Kevin Botsford        Milo G. Coerper              Ulf H. Dolling
   Acculto                         Letha & John C. Barber         Nancy L. & John D.             Arthur J. Cohen              Thomas A. Donahue
Eliz M. Adams                      David A. Bardes                  Bourque                      Harold Cohen                 Charles Dorsch
Robert E. Adams                    Stanley H. Barer               Denis A. Bovin                 Aaron Coleman                Janet Dreier
Linda S. & Wayne L.                Ronald H. Bargatze             George E. Boynton              Jan C. Collins               John F. Dresch
   Adamson                         Curtis H. Barnette             Bradley Associates             William S. Comanor           Jean J. & James J. Driscoll
Susan & Jason I. Adleman           Richard Barry                  Elizabeth O. & Frank W.        Comm to Reelect Senator      Patricia Duberg
Mr. & Mrs. Robert B.               Marie & Martin Bartkowski        Brand                           Bruno                     Henry L. Duffus
   Aikens† ▲                       Deborah & Richard              Rudolph K. Braun               Robert B. Congdon            Kimberly & David Dunn
Susan & Ronald C. Albrecht           Bartrem                      David S. Broder                John M. Conroy Jr.           John C. Duryea
Jane A. & Richard H.               Charles Bauer                  Thomas F. Brodesser Jr.        Joseph P. Conte              Alvin J. Dykhouse
   Albright Jr.                    Patricia* & Robert P.          Wendyce H. and William R.      Barbara A. & John R.         Leatrice & Melvin B. Eagle
John T. Alger                        Bauman                         Brody                           Cookson                   William Ebersole
George A. Allard Jr.               Deidre L. & Eugene Bay         Herbert J. Broner              Mr. & Mrs. James Conney      Marylou K. & Alan R.
Jeremy Allen                       Michael Baylson                Alvin J. Brown                 Elizabeth Cooper                Eckels
Pamela J. & Peter G. H.            William P. Beatson Jr.▲        Arnold Brown                   Marvin A. Cooper             William R. Edmunds
   Allen                           Patsy Beck                     Janice Reid & Douglas T.       Mr. & Mrs. Thomas E.         Lucy & Howard Eiffert
Judith & Walter W. Allen           Alice B. & George L.             Brown                           Cooper                    Rex L. Eiffert
Elizabeth P. & Alvin V.              Becker Jr.                   John D. Brown                  Pamela F. & John C.          Laura A. Eisdorfer
   Alsobrook                       Edward R. Becker               Rodney D. Brown                   Corckran Jr.▲             Janet E. & Norton A.
Rhoda & Michael M.                 Mary Ann & Bill Becker†        Mr. & Mrs. Tilmon F.           W. M. Corley                    Eisenberg
   Ambach                          Teresa A. & Charles E.           Brown                        Frank Cossaboon              Barbara & Marvin
Elizabeth A. & Gordon M.             Bedford                      Bettye & Ken Brumit ▲          Nathaniel J. Couch              Eisenstadt
   Anderson                        Dorothy W. & John P.           Carlo Brunacci                 Gretchen & Nelson            Stuart E. Eizenstat
Harold E. Anderson                   Bedor                        James B. Bryan                    Cover Jr.                 Marilyn H. & Paul D.
Janet R. & Robert N.               Renee E. & Robert A. Belfer    Peter M. Buccieri              Frank D. Cox Jr.                Elliott
   Anderson                        Reed Bell Sr.                  Arlene K. & Paul Buck          Gary Cox                     J. Leon Ellman
James W. Apthorp                   Leroy D. Bence                 Georgiana G. Buck              Gregory R. Cox               George Elmore
Alan Aronson                       David S. Benedict              Mr. & Mrs. Russell T.          Robert H. Craft              John F. Elsen
Natalie A. & Sidney                Roger Benedict                   Bundy                        Betty & L. Scott Cram        Jerome S. Engel
   Ashmore                         John R. Benfield               Ann & George Bunting           Stuart P. Cram               Carl C. Engle
Edward R. Aus                      Ann E. & Royce Benjamin        Sharon A. & Clifford F.        Rev. Richard E. Cramblitt    Calista E. & E. Stanley*
Jerome Averbuch                    Sheryl L. Benjamin               Burg                         Linda F. Crawford               Enlund
Steven H. Axelrad                  Patricia R. & Robert J.        Edward D. Burger               Charles E. Creamer           Karl A. Erb
Jonathan A. Azrael                   Bennett Jr.                  Nancy A. Burgess               John Criscuolo               R. Christian B. Evensen† ▲
Curtis B. Backus                   Mitchell C. Benson             Rose M. Burns                  Martha D. & John S.          Soga Ewedemi
Bajaj Auto Limited                 Michael D. Berg                Laura R. Burrows-Jackson          Crute Jr.                 Donald R. Ewing
Barbara V. & John L. Baker         Helene & Adolph Berger           & A. Michael Jackson         Dorothy C. & James L.        Andre Ezis
G. Leonard Baker Jr.               Patricia M. & Victor A.        Dewey Bushaw                      Currie                    Richard A. Farber
Mr. and Mrs. Robert C.               Bergwall                     James J. Busse                 Jim Dale                     Thomas Farber
   Baker Family                    Muriel V., Ph.D. & Alfred R.   Edward M. Buxbaum              Patrick H. Dallet            James E. Farney
   Foundation† ▲                     Berkeley III ▲               Robert E. L. Calhoun           Geralyn & Mark Daly          Florida Association of
E. M. Bakwin                       Eugene L. Bernard              Sally R. & John G.             Alfred Damato                   Student Financial Aid
Carol Bald                         George A. Bernhardt              Campbell                     David A. Dammen                 Administrators, Inc.
Genevieve L. & Edmund G.           Beverly J. & Anthony J.        William A. Capella             Aaron M. Daniels             Lucille S. Faulk
   Balducci                          Bernitsky
† Founders’ Circle       Brady Advisory Council   * Deceased
1 4 PROSTATE CANCER DISCOVERY                                   WINTER    2005

Stephen A. Fennell                 Carol B. & Raymond E.          Rosalie Hakker              Jack Holcomb                  Robert L. Kaufman
Larry Fenster                         George Jr.                  Carolyn & Richard Haley     Bonnie L. & Stephen P.        Judith Kaufmann &
Gonzalo Ferrer-Rincon              R. Paul George                 Robert A. Hall Jr.             Holmes                        Ambassador George E.
Antonia L. & Richard F.            Shirlee M. Gerber              Nancy & Robert E. Hall      Robert K. Holyer                 Moore
   Ferrucci                        Darlene A. & Walter B.         Dorothy M. & Alan M.        F. Robert Hood                Marvin M. Keagy*
Diana M. & Seymour S.                 Gerken                        Halperin                  Earl H. Hopgood               James S. Keelty III
   Feuer                           Marc Gershman                  Steven J. Halperin          Alan & Karen Hopkins          J. Michael Keenan
Jeanne & Kenneth Fibus             David M. Gerstein              John V. Halsey              Martin Hopkins                James F. Kegg
Thomas W. Filardo                  Felicia & Charles Gervais      Lapsley W. Hamblen Jr.      Hopping Green & Sams          Mark C. Kelly
Vera R. Filby                      Timothy K. Getty               Vivian & Carl Hamburg          Professional Association   Vincent C. Kempf
William G. Finard                  Nancy H. & Carl S. Gewirz      Mr. & Mrs. Richard Mark     Mary E. & Neil G. Horn        Carol S. & James Kennelly
Patrick Finerty                    Jane Gibbons                     Hamlin                    Brent L. Horsley              Deborah G. & Norman
Joann & Gary C. Fink               John A. Gibbs                  Judith E. Hanlon            Louis Horst Jr.                  Kenneway
Daniel Finkelstein                 Nancy H. & Charles D.          R. Timothy Hanlon           Susan S. & W. Carl            Rolland D. Kerr
Michael A. Finn                       Gilbert                     William C. Harbin Jr.          Hossfeld Jr.               Toba S. & Lawrence A.
Thomas D. Finnigan                 Steven J. Gilbert              Thomas G. Hardie            Samuel C. Hottle                 Kerson
Myers N. Fisher                    Paul W. Gimmler                William M. Hardy III        Richard J. Howe               Nancy A. & William L.
Robert Fisher                      Francis J. Glick               William J. Harmount         Penny C. & Albert C.             Kimsey
Michael E. Fishman                 Leo R. Goertz                  Audley Harris                  Hubbard Jr.                Herb King
John N. Fix                        Isidore L. Goldberg            Edward A. Hart              Carolyn & Laurence T.         George G. Kirkpatrick Jr.*
Mary M. & Neil Flanagin            Betty I. & Larry Goldblatt     Lorraine & Gary Hart           Huber                      Gregory Kirsch
Helen P. & Ernest G.               Stanley Goldenberg             Gary W. Hart                Charlton C. & F. Patrick      Peter F. Klaren
   Fleischmann                     Maxine L. & Joel K.            Richard A. Hartley             Hughes †                   Sue S. & Irwin M. Klau
Carrie B. & David Fletcher            Goldstein                   Bruce W. Hartman            Michael D. Huke               Eugene Klee
Gloria W. & George E.              Stephen Goldston               Howard N. Hartman           Frederick C. Hunte            Joan & Joseph Klein Jr.
   Fletcher                        James Goodfellow               Harris L. Hartz             Samuel P. Hunter              James W. Knapp
Florida Power & Light              Samuel Goodloe                 Janice L. Lindsay-Hartz &   Geoffrey R. Hurd              James M. Kniskern
   Group                           Diane J. Goodman                 Steven Hartz              Harriet Hyams                 George Konstantinidis
Florida Rock                       James R. Gordon                Darrell Harvey              Henry J. Hyde                 Penny & John Kopf
   Industries, Inc.                Judith B. & Frank W.           Brian and Phyllis Harvey    Joseph Ichiuji                Igor J. Koralnik
Israel J. Floyd                       Gordon                        Foundation†               Edward J. Imperatore          Charles Kozloff
Harry T. Fogle                     Norman N. Gottlieb             Lenore V. Hash              International College, Inc.   Manus C. Kraff
Edward A. Fontaine                 Ora Gourarie & Udi Shore       David E. Hassinger          Joseph F. Ireland III         Morris J. Kramer
Horace C. Ford                     Christine R. & John C.         Kenneth B. Hauser           Sondra & Alan Isen            Sidney D. Krasner
Charles S. Foresman                   Graff                       Chester Z. Haverback        Carol & Harold D. Isen        Emily Kraus
Adelaide & Joseph Forte            David R. Graham                Lois R. & James H. Heald    Seymour D. Israel             Joseph H. Kravitz
Lewis W. Foy                       James K. Graham                David D. Heard              Martin S. Jacob               Daniel H. Krivit
Edward B. Frankel                  Peter J. Graham                Gloria C. Hegeman           E. R. James                   Robert F. Krohn
Robert Frankel                     Herbert A. Granath             Clifford J. Heilig          Delores Ann K. & Robert L.    Ralph Kuhn
Frederick M. Franks Jr.            Michael L. Grandelli           Maryann & David R.             James                      Kenneth Kuhnle
Keith S. Franz                     Grass Family Foundation          Heilman                   Jane M. & William R. James    Alicia & Robert D.
Maxwell M. Freeman                 Carolyn R. & Randolph L.       Richard P. Heiman           Herbert L. Jamison               Kunisch Sr.
The Walter Henry Freygang             Greasham                    Judy & Ralph Heltzel        Anthony J. Jesatko*           Michael B. Kurtz
   Foundation                      Dana & Richard L. Green        Carolyn G. Henderson        Ann E. & John H. Mc           Mr. & Mrs. Marvyn Kussner
Charles A. Friedman                Mr. & Mrs. Donald A.           Karen A. & Frederick L.        Dermott Foundation         Doris & Don Kyne
Stanley Frost                         Greenawalt                    Henderson                 Jerome Johns                  Gary L. Laabs
Edward Furdak                      Harold D. Greenberg            George L. Henderson         F. M. and D. A. Johnson       Donald G. La Casse
Rosemary & Richard                 Susan B. & Sanford D.          James D. Henderson             Family Fund of the         Joseph H. Lackey
   Furman ▲                           Greenberg                   John B. Henderson              Grand Haven Area           Rachel and Mark Ladenson
Annie W. & John Furrer             Sheila & James Greenway        Merle R. & Elrod J.            Comm. Fdn.                 Katherine S. LaFrance
Casey Gahan                        Mr. & Mrs. Kenneth L.            Hendricks                 Dale Johnson                  Mr. and Mrs. Lawrence
Mary V. & Edward W.                   Greif                       Elizabeth W. & Richard M.   Donald A. Johnson                Laikin
   Gahan                           Mr. & Mrs. Leonard L.            Henry                     Dorothy A. & F. Martin        William T. Lake
Gainesville Raceway                   Greif Jr.                   H. Kirk Henry Jr.              Johnson                    Douglas M. Lambert
Gainsville Alachua County          Peggy W. & W. Marvin           Heather C. & Patrick        Glenn H. Johnson              Marian & Sidney
   Association of                     Gresham                       Henry † ▲                 James L. Johnson                 Lansburgh
   Realtors, Inc.                  John Gribbel III               Charles E. Herget Jr.       Ray E. Johnson                Gloria & Ralph W.
H. Rowan Gaither                   David-Alexandre C. Gros        Steven T. Herman            Patsy S. & Richard S.            LaRovere
Susan Galandick & Hiram            Linda & Rich Grossi            Kenneth R. Hess                Johnson ▲                  Allan R. Larrabee
   C. Polk Jr.                     Rozelle & Barry Grossman       Stephen H. Hess             Allen N. Jones                Michael J. Lasalandra
Charles W. Gale                    Gary Grosvalet                 Kalman R. Hettleman         Hugh R. Jones                 Allen L. Lastinger Jr.
Barbara G. & Douglas               Albert Guidry                  Ann B. Hiban                W. Braun Jones                Martha J. & Juan K.
   Gallant                         Leo E. Gulley                  Marita L. & Thomas J.       Rex A. Jordan                    Laurilla
George H. Gallup Jr.               David E. Gumpert                 Hickey Jr.                R. Tom Joyner                 Connie & Andrew M.
Maryrose & David Gans              Meredith S. & Bradley H.       Jody & Michael W. Hill      William R. Kadan                 Lawler
Cynthia & Gary E. Gantz               Gunter                      Carla & Roderick Hills      Melvin M. Kaftan              Ivan L. Lawyer
Anton S. Gardner                   Donna & Edwin                  Roger C. Hill Sr.           Donald H. Kaich               Harvey A. Lazar
Nancy G. & Aaron Garnitz              Gustafson Jr.               Russell Hill                Jerold Kaniuk                 Cynthia R. & Sean Leahy
E. E. Gasque Jr.                   James W. Gustafson             James V. Hirsch             Robert B. Karnes              Harry P. Lebow
Sidney B. & Caleb F.               Debbi A. Haacke                Helene & T. Donald          Nabil D. Kassir               William W. LeCates
   Gates Jr.                       Stuart L. Haas                   Hirschfeld                George Kasten                 Carol & Mark Lederman
Arthur Gatty                       Mr. & Mrs. Willard             Jong Ho                     Walter Kasten II              Richard C. Lee
Geraldine & Leonard                   Hackerman                   Morgan D. Hodgson           Claudia H. & Dana R.          Emily D.& William Leete
   Genovese Sr.                    Carlos A. Haeussler            Charles L. Hofeller            Katnick                    Sally L. & Charles F.
                                   Patrick Hagan                  Jules M. Hoffman            Judy H. & David S. Katz          Lehman

† Founders’ Circle       Brady Advisory Council   * Deceased
                                                                             WINTER      2005     PROSTATE          CANCER       DISCOVERY          15

Barbara L. & O. Bernard           Dorothy B. & George            Mr. and Mrs. Frederick O.     Grace B. & Warren E.          Mr. & Mrs. Joseph F.
   Leibman                          Martel                         Mitchell                       Ousley                        Rascoff ▲
George A. Leighton III            Kay C. & Frank J. Martin Sr.   Deborah G. & Searle E.        Rachel & Don B. Overall       Mrs. Frank E. Rath Sr.
Louis J. Lekus                    Maryland Independent             Mitnick                     Barry Owen                    The Frank E. Rath,
Donna D. & Robert C.                College and University       The MJK Family                Sheila M. & Ralph E. Owen        Spang & Company
   Leland Jr.                       Association                    Foundation                  George Ozturk                    Charitable Trust
Ramie L. Lepler                   Tammy & Dan A. Mayer           Beverly & Paul Mohr           Rupert Palmer                 Dan Raymond
Mr. and Mrs. J.E. Letchman        G. Steuart Mays                Patrick A. Molony             James F. Palo                 Stephen Reddy
Alan M. Levin                     Marion S. Mays                 The Ambrose Monell            Lucas Papavasiliou            Ann M. Reed
Michael L. Levin                  Grace & Joseph Mazzarella        Foundation                  Sarah C. Paradies             S. Peter Regenstreif
Alan M. Levine                    Rosanne B. McAboy              Michael J. Monnacio Jr        Edward L. Park                Jean W. Reinhart
Susan J. & Jon H. Levinson        Anne & Joseph McCann ▲         Spencer Montgomery            Ildong C. & Ki Suh Park       Rose-Lee and Keith
Robert G. Levy                    James P. McCarron Jr.          Leslie Moore                  Beverly A. & Clare O.            Reinhard ▲
Guy W. Lewis                      Jacinta P. & David             George E. Moose                  Parker                     Linda S. & Lawrence R.
Harvey G. Lewis                     McCarthy                     James H. Moran                Joseph Parnes                    Remensnyder
Shelley & Wallace L.              George B. McCeney              Maria P. & Eben Morgan        John Paterakis Sr.            Muriel D. & Irving L.
   Lewis Jr.                      William E. McClure             Ann & Kenneth Morrill         Alan J. Patricof                 Resnick
Jose A. Liceaga                   Melissa McDaniel               Morton L. Moss                Donald W. Patterson           Stewart R. Reuter
Merrill S. Lichtenfeld            Stephen S. McDermott           Jacek L. Mostwin              Lyle Patzkowsky               Charles R. Rice
Steve Lincoln                     Beverly A. & Gary L.           Denis J. Mullane              Edwin S. Pearlstine Jr.       Johnnie L. Rice
Jon R. Lind                         McDonald†                    Thomas J. Munroe              Willard H. Pearsall Jr.       Ridgway Roof Truss
A. F. Lindenstruth                Thomas G. McElrath             Barbara E. & Michael C.       Nickolas S. Pekatos              Company
Cheryl & Robert R.                Robert L. McElroy                Murphy                      Aldo Brachetti Peretti        Richard W. Riley
   Lindgren                       Lee J. McFadden                James Murphy                  John M. Perry                 John L. Roberts*
Kenneth L. Lindmark               William B. McGinty             Jane G. Murphy                Patricia & Noel L. Peterson   Walter B. Roberts Jr.
Julie Lipper                      Diane C. & Timothy             Susan & Mark B. Murphy        Mr. & Mrs. Ronald R.          Arthur Robinson
Paul S. Liscord Jr.*                McGowan                      Beth W. & A. Ross Myers † ▲      Peterson                   Bertram Robinson
Paul S. Liscord III               Peter E. McGrath               Theodore A. Myers             Philadelphia Brokerage        Maureen A. & Albert T.
Bancroft Littlefield              Daniel McInerney               Grace & Brian C. Myhr            Company                       Robinson
Anthony L. Llewellyn              Roland B. McIntosh             Tillman Mynatt                Derwyn F. Phillips            Charlotte G. & Morris
Earl G. Loch                      Margaret J. & Kenneth N.       Charles J. Nabit              John Phillips                    Robinson
Martha J. & Frazer W.               McKelvey                     Kit Narodick                  Eleanor A. & Harley           Mr. and Mrs. Robert J.
   Lockhart                       Thomas J. McKnight             Douglas Nash                     Pickens                       Robyak
Arthur B. Lofton                  Brian E. McManus               National Association of       Roberta & Steve R.            Bert Rodgers
Richard Lohrens                   Harry M. McMillan                Independent Colleges           Pieczenik                  Eleanor B. & Walter C.
Clarence E. Long                  Jane & F. David                  and Universities            Guy B. Pierce                    Rodgers
Rene Lopez-Duprey                   McNamara Jr                  National Hot Rod              Robert T. Pizzano, Sr.        Rebecca L. & Michael
Herman R. Lopyan                  Willard C. McNitt                Association                 Roy W. Plekenpol                 Rodman
Sorge Losch                       Howard B. Means                Bruce F. Nelson               Philip G. Plotica             Shirley A. & Ivan A.
Paul V. Losick                    Roger W. Mehle                 Leonard M. Nelson             Leslie P. & Gary Plotnick        Rodriguez Cabra
John Loudon                       Joel S. Meisel                 Merle R. Nelson               Diana & Dirk Poeschel         Stephen C. Roe
Richard B. Lowe III               Edward C. Melby Jr.            Rimma & Leonid                Joel I. Polin                 Gil Rogers
Mark Lowenthal                    George J. Mellendick             Nemirovsky                  Irene & Abe Pollin            Glenn R. Rogers
Carol L. & Eugene A.              Alan Melowsky                  Thomas B. Nenninger           Jayne L. & Alan Pollin        Evelyn D. & Ernest A.
   Ludwig                         Harriet H. & M. Edward         Rosalind & Charles            Richard K. Poole                 Rohana
Lynn & Robert Luft                  Melton                         Neustein                    Poole McKinley and Blosser    Robert D. Romeril
Saralyn & Walker W. Lundy         Bruce A. Menge                 Anthony L. Neves              Patricia & George Poporad     Audrey C. & William H.
Warren B. Luttrell                Jacob Menten                   William A. Newsom             Thomas S. Porter                 Ronnermann
Katherine MacDonald               Kenneth G. Menzies             Stavros S. Niarchos           Marvin Portnoy                Drew P. Ronnermann
Earle I. Mack                     Robert W. Mercer                 Foundation                  Lois & John Post              Beth Rose
Ann S. & Clark F.                 John C. Merrill                Paul H. Nielsen               Jon L. Powell                 Odell H. Rosen
   MacKenzie                      John G. Metcalf                Peter T. Nigri                Diane E. & Larry M. Powell    Dorothy & Henry
Carla B. & Bruce H.               Jacklyn & Carl Meurk           Mr. & Mrs. Barry Nolan        Nancy R. & William J.            Rosenberg
   MacLeod                        Harvey M. Meyerhoff            James D. Nolan                   Powell                        Foundation, Inc.
Ian K. MacPherson                 Stacy L. & James P. Milanesi   Frances & Henry R.            Peter Presland                Herbert Rosenberg
Roger W. MacWilliams              John I. Miles                    Nolte Jr.                   Ralph M. Prettyman            Lana L. & Jack E. Rosenfeld
Robert V. Magdaleno               Edward T. Miller               Robert D. Novak               Douglas R. Price              John Rosenthal
John Magnier                      Keith Miller                   Rudolph A. Novello            Ellen V. & Joseph B. Price    Ruth A. & Raymond P.
Kristie & Jerry K. Mahan          Lynne R. & Edward D.           Brenda S. & Irwin J.          Pricewaterhouse Coopers,         Roshkoff
Ettore Maina                        Miller                         Nudelman                       LLP                        Horace Ross
Patrick D. Maines                 Maria Miller                   James G. O’Connor             Pride Enterprises             Zelly D. Ross
John F. Maloney Jr                Margaret K. & Robert S.        John J. O’Hara                Darrell Prochaska             Vladimir Roth
Rita J. & Gil Manfuso               Miller                       Donald O’Kieffe               Maurice F. Prout              Thomas Rothwell
Janie & Jon L. Mangus             Marvin A. Miller               Mary P. O’Leary               Charles L. Purdum             Mindy & Robert Rovinsky
James Manzelmann                  Merle L. Mills                 Richard O’Leary               Purvis Gray and Company       Linda Rowe
Trisha S. & Rabbi Frederic        Kay & Pat Milmoe               Nancy & Jim O’Neal † ▲        Kathleen & Clarence C.        William E. Rowe
   J. Margulies                   William J. Milner              Patricia F. & Otto G.            Pusey                      Tara G. & Anthony J. Rucci
John R. Margulis                  Mr. & Mrs. Douglas A.            Obermaier                   Puth Family Foundation        Richard Rudikoff
Jeanne K. & Richard Markey          Milroy                       Martha W. & Girard F.         Martha & John P. Quay         Basil M. Rudusky
Raenel & Steven F.                Minister Machine                 Oberrender Jr.              Robert Quigley                Hans J. Ruehsen
   Markstein                        Company                      Nancy & Morris W. Offit       Gale C. Quist                 Jerald J. Rumsey
Mary Ellen & James Marpe          Seymour D. Mintz               Michael Opake                 Joan & Carl M. Raab           J. N. Russell
Richard L. Marrapese              Mirabella, Smith and           William Opdyke                James E. Radja                Marcia G. & Robert W.
Marsh USA, Inc.                     McKinnon                     Harvey Orlin                  Herzl Ragins                     Russell
                                  Greg Mitchell                  Berna L. Osnos*               Thomas S. Ragsdale

† Founders’ Circle       Brady Advisory Council   * Deceased
1 6 PROSTATE CANCER DISCOVERY                                    WINTER     2005

Laurie S.* & T. Edgie              Morton I. Silverstein           Gary E. Talles
   Russell III                     David Henry Simon ▲             Taylor Family Farm
Edward Ryan                        Robert L. Simon                 Virginia & Julius Tauber
Wallace Ryzenga Jr.                Richard Simons                  Benjamin G. Taylor
Joseph F. Rzepka                   Archie D. Simpson               Carol & E. Duncan Taylor
Leonard Sachs                      Stephen A. Siwinski             Kim & J. Frank Taylor
Mortimer D. Sackler                Lillian & Fred N. Six           John W. Taylor
Susan R. & Sanford J.              Edward J. Skeens                Julia C. & Mark J. Taylor
   Sacks                           E. Scott Smith                  Thomas S. Taylor
Jose Said                          Ellen W. & Preston H.           Wade W. Taylor
Jane C. & Edwin C. Saiontz            Smith                        Barbara M. & Edward M.
Mr. & Mrs. Paul W.                 Ethan A. Smith Jr.                Templeman
   Sandman †                       Judith G. & James F.            Belmonte Tenaglia
Paul R. Sandquist                     Smith Sr.                    Harvey L. Tesch
Alexander V. Sandusky              Janet G. Smith                  Margaret J. & Robert J.
Avery & Steven K. Sargent          Leonard B. Smith                  Theis Sr.
Gerald J. Savage                   Seymour S. Smith                Andrew B. Thomas
Lorraine Schaab                    Lee A. Snyder                   K. Leigh & Charles W.
Joanne & Gerald Schackow           Stephen J. Snyder                 Thomas
Mary Dean & Eric K.                Robert P. Sommer                Mary Ann J. Thomas
   Schaumloffel                    South Carolina                  Melvin Thomas
John P. Scheuren*                     Independent Colleges         Robert Thomas
William J. Schifino                   and Universities, Inc.       James K. Thomson
Kent E. Schiner                    Lloyd J. Spafford               Mr. & Mrs. Charles B.          Discovery happens every day at the Brady Urological Institute
Barbara & Gene Schmitt             Gertrude H. & Charles O.          Thornton Jr. †               – in the laboratory, the operating room, and the clinic. All of
James R. Schmitt                      Spang                        Nicholas L. Tilney             it is directly inspired by our patients, and the dedication of our
Howard M. Schober                  Craig S. Specker                Joy & Leonard Toboroff         physicians and scientists to helping them beat prostate cancer.
Andrew W. Schulman                 David L. Spiker                 Edward Tokar
Marjorie B. & Robert P.            Jack F. St. Clair               Robert L. Toner
   Schulman                        Miriam M. & Munsell W.          Frederic C. Towers             Rev. William J. Watters, S.J.      Connie & Brison R. Wood
Frederic T. Schwartz                  St. Clair                    Brian F. Trainor               Basil J. Weedon                    Mary K. & Michael V.
Irene & Bernard L.                 Michael L. Stacey               Alison & James Traub           Timothy T. Weglicki                  Woodall
   Schwartz †                      Inge, M.D., & John R.           James Travis                   Sir Mark & Lady Weinberg           Anthony C. Woodruff
Joshua I. Schwartz                    Stafford                     Shelia H. & Richard V. Trefz   Marla Weinrieb                     John W. Wright
Peter Schwartz                     George H. Stair Jr.             John B. Trevor                 Edward I. Weinshelbaum             Wyeth Corporation
Michael I. Schwartzman             Susanne D. & David W.           Robert L. Trimpi               Frank M. Weiser                    John S. Wyman
Ardis P. Schwarz                      Stanley                      William E. Turner              Howard I. Weissleader              Marilou W. & Donald T.
Dorothy & Paul Schwebel            Walter Stapleton                Margaret K. Tyler              William H. Wells                     Wynne
Virginia & Warren L.               Polly & Walter J. Stark Jr.     Roger E. Tyler                 Barry Wendell                      Emily E. Yaron
   Schwerin                        William A. Starr                Fred W. Ulrich                 Peter D. Wertz                     Ronald G. Yelenik
Elizabeth M. & Donald B.           Mark Stautzenbach               Mr. & Mrs. Jon Wallace         W. Galen Weston                    Robert H. Yoakum
   Scott                           Steelcase Foundation              Upton                        Michael C. Wheeler                 Eleanor H. & Stuart H.
Jon J. Seal                        Victor Stein                    US Education Finance           David T. Whelan                      Yuspa
James Seavitt                      S. Ty Steinberg                   Management                   Branka & John W.                   Robert P. Zabel
Josephine I. Seberg                Daniel T. Stevens                 Corporation                    Whisnant                         Mr. & Mrs. Marvin Zale ▲
M. Gerald Sedam II                 Ray Stevens                     Thomas J. Van Meer             Katherine O. & B. Hunt             Bonnie & Robert S.
Jeffrey B. Segal                   Samuel C. Stokes                George Vande Woude               Whitbeck Jr.                       Zalkowitz
Paul E. Segal                      Edward D. Stone Jr.             Michael A. VanDerworp          Mark Wienpahl                      Vivian L. & George H.
Sumner Segal                       Carol R. & Edward A.            Mariana & Vardis J.            Shirley & Jerry M. Wilde             Zalzal
Wilber Seidel                         Storey                         Vardinoyannis                Thomas G. Wilkinson                Alan J. Zatz
Georges I. Selzer                  Merrell L. Stout                Nick M. Vasilatos              Thomas S. Will                     Peter E. Zdenek
Ambassador and Mrs.                Morris Straitman                Jan A. & Richard Vernet        Robert Wille                       Debra L. & John H. Zeller
   Marvin Sembler                  Margaret Dorrance               Richard G. Vernon              Charles T. Williams III            Frances & Robert L.
Thomas S. Sennett                     Strawbridge Foundation       Carol A. & Paul G. Viall Jr.   G. Kimball Williams                  Zielsdorf
Jeff Sessions III                     of PA. I., Inc.              Luciana & Joe Vittoria † ▲     Marjorie J. Williams &             Norman Zinner
Stewart Share                      John F. Strobel                 Norman F. Von Herzen             Walter L. Wright
Fred I. Sharp                      Mary L. & Stephen O.            Tonya U. Vu                    Owen W. Williams                   Every effort has been made
The Peter Jay Sharp                   Stubbs                       Alfred J. Wadanoli             Robert W. Williams Jr.             to ensure that you have been
   Foundation †                    Susan M. & Donald               Laura L. & Kirk Wade           Karen H. & Wesley S.               listed accurately and according
James M. Shea                         Sturm ▲                      Gary W. Waicker                  Williams Jr.                     to your wishes. If an error has
L. David Shear                     Carolyn & William Stutt† ▲      Harry J. Waldman               Betty S. & Everett S.              been made, please accept our
Madalyn & Frederick Shear          Hazel & A. P. Sullivan          Richard H. Walker                Williston                        apologies and notify us directly
Theodore P. Shen                   Richard J. Sullivan             Susan S. Walker                Robert Wilson                      at (410) 516-6160.
Elisabeth A. & Edward P.           Frances & Thomas J.             Linda & Jay L. Wallberg ▲      Abigail K. Winans
   Sheridan                           Sullivan                     Allan J. Waltzman              Nancy E. & Harold Winch
Marilyn & Budge                    Sunshine Fund – Circuit         William D. Wampler             Mildred A. & E.E. Winne
   Sherwood                           Court Judges                 Anne A. & Terry Waranch        Melvin H. Winograd
Lynne Sherwood                     Susman & Asher                  Esther* L. & Ralph T.          Donald F. Winslow
Kyun Shin                             Foundation                     Warburton                    Alan C. Winters
Robert D. Shlens                   Mr. & Mrs. W. Clarke            Maryann K. Ward                Francine S. Winzelberg
Laura & John Shmerler                 Swanson Jr.                  Marilyn A. & Raymond C.        Richard C. Wise
Jonathan L. Shurberg               Lawrence Szantor                  Ward                         Alan M. Wiseman
Henry P. Sideropoulos              John R. Talbott Jr.             Bruce Wardell                  David J. Witham
Blanche W. & Robert                The Tall Pines Charitable       Burton Wasserman               Charles M. Wolfson
   Siegfried                          Foundation                   Frank M. Watkins               Charles Wolverton

† Founders’ Circle       Brady Advisory Council   * Deceased

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