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The Holy Grail, for scientists studying evolution,
is the idea of a “missing link,” a creature somewhere between
man and ape, to explain how humans came to be. Scientists studying
prostate cancer are also looking for missing links—more than one,
certainly—to explain the complicated journey through which a normal
cell evolves into a cancerous one. What lies between Point A and
Point B?
One step before prostate cancer is PIN, prostatic
intraepithelial neoplasia, or “funny-looking” cells that aren’t
normal, but aren’t quite cancerous. One likely step before that,
as pathologist Angelo De Marzo, M.D. , Ph.D., discovered a couple
of years ago, is PIA, proliferative inflammatory atrophy—cells
that appear to be shut down, or atrophied, and are surrounded
with inflammation. PIA cells, despite their appearance, are actually
volatile, with wildly fluctuating levels of glutathione-S -transferase
p, which protects against prostate cancer.
Is early inflammation of the prostate an important step—even a
missing link— to cancer? And is this inflammation a “done deal,”
or is it reversible?
Oncologists Michael A. Carducci, M.D. , and Theodore
DeWeese, M.D. , of the Brady Urological Institute and the Kimmel
Cancer Center, interested in the idea of reversing the steps leading
to cancer through “chemoprevention,” are hoping to find out.
They have started a clinical trial, funded by the
National Cancer Institute, of antiinflammatory drugs called COX
(cyclooxygenase) inhibitors—a class of drugs that includes NSAIDS
(nonsteroidal antiinflammatory drugs) and even plain old aspirin.
The particular drug in this trial, a selective COX-2 inhibitor
(which has fewer side effects than aspirin and other drugs in
this class) called celecoxib, was developed as a treatment for
arthritis. “But it turns out,” says Carducci, “that the COX-2
inhibitors also interact heavily with the pathways that are important
for cancer progression. The idea, bolstered by research from Angelo
De Marzo, Bill Nelson, Ted DeWeese, and others, is that early
inflammatory injury—and whether or not the body’s able to repair
it—may be the next step to forming cancer. And new evidence suggests
that when there’s inflammation, growth factors are produced that
promote blood vessel growth, and this also may increase the likelihood
that cancer will develop. So it’s becoming increasingly clear
that maybe just blocking this pathway could delay disease. ”
COX inhibitors are known to lower someone’s risk
of developing colon cancer; they also may help prevent esophageal
cancer, and some recent studies suggest that men who regularly
take aspirin and other COX inhibitors are less likely to develop
prostate cancer.
“Our research (done in collaboration with Brady
molecular geneticist Bill Isaacs) suggests that if these inhibitors
do work, they don’t seem to be working by directly affecting the
cancer cells themselves,” says De Marzo, “because the target protein
of the inhibitor is not present in prostate cancer cells. It’s
only present in some of the inflammatory cells, the white blood
cells, and in the PIA cells themselves. So it suggests that if
these drugs really do inhibit prostate cancer—if these are little
fires burning in the prostate—this might put them out.” These
early cells, De Marzo notes, are a different kettle of fish altogether
from advanced cancer cells.
“We
want to see whether this is something we should be giving
very early in the disease, to someone who’s at high risk,
or if taking this could help prevent prostate cancer, like
an aspirin a day for your heart. ” |
“When we examine a prostate that’s been removed
for cancer—even in the ones where there is not a lot of cancer—
we see several little, separate cancers,” says De Marzo. “If we
could decrease the rate of formation of these little cancers—prevent
new lesions from forming—we might stop the big cancers. ”
In Carducci’s new study, which is “double- blind”—meaning
the doctors don’t know who is getting the drug, and who is getting
a placebo—men who are scheduled to undergo radical prostatectomy
will be given celecoxib for about six weeks, from the time their
cancer is diagnosed until the time of surgery. De Marzo, explaining
the need to make the study “blind,” quotes Brady scientist Don
Coffey, Ph.D. “As Dr. Coffey says, you don’t see with your eyes,
you see with your mind, what you expect to see. If you can’t possibly
see it, that’s the only way to make it really valid. ”
“The idea,” says Carducci, “is to look a
short-term exposure, and see what the effect of the drug is on
inflammation, angiogenesis (growth of new blood vessels to feed
the cancer), DNA damage, and cell proliferation. ” After the men
undergo surgery, De Marzo will examine the removed prostate tissue.
If the COX inhibitor shows promise, the study will
be expanded. “We want to see whether this is something we should
be giving very early in the disease, to someone who’s at high
risk, or if taking this could help prevent prostate cancer, like
an aspirin a day for your heart,” says Carducci.
De Marzo is conducting longer-term laboratory studies
to see whether giving COX inhibitors can prevent prostate cancer
in rats. “It would be nice one day,” he envisions, “to give this
to younger men, in their 30s and 40s, and say, ‘you don’t have
cancer yet, but you have a high risk. Start taking these fairly
nontoxic drugs, and they may prevent your prostate cancer, and
incidentally, prevent colon cancer. We’re not there yet, but that’s
the real potential payoff. ”
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