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Prostate Cancer Find
Points to New Drug Target
Scientists have uncovered
a cruel twist of fate in men who have
advanced prostate cancer.
Doctors have long known
that the medications they use to treat
prostate cancer effectively for one to two
years inevitably fail, leaving patients
with few treatment options as the disease
progresses, killing more than 30,000 men
in the United States alone every year.
Now scientists have
discovered that at least one such
medication has a completely unexpected
side effect: the compound actually turns
on a molecule known to cause cancerous
cells to grow. The work, which earned an
award for outstanding research from the
American Urological Association, is
described in the November 1 2002 issue of
the Journal Cancer Research.
"It's a real surprise,
that the same compound that kills cancer
cells also makes them grow," says
Chawnshang Chang, Ph.D., corresponding
author and director of the George Whipple
Laboratory for Cancer Research at the
University of Rochester Medical Center.
"The effect of the drug reverses
completely."
Treatment for men whose
prostrate cancer has spread to other parts
of the body takes advantage of a unique
characteristic that makes prostate cancer
cells vulnerable: usually they depend on
testosterone for survival. When doctors
slash the supply of the hormone, most of
the cancer cells die.
After surgery, radiation,
and other treatment options, doctors try
chemical or surgical castration or
hormonal therapy, which knocks out most of
a man's supply of testosterone.
Oftentimes, to prevent the little
remaining testosterone from feeding the
cancer, doctors supplement this treatment
with a drug known as an anti-androgen,
which blocks the molecule through which
testosterone works, the androgen receptor.
But some cancer cells
survive, and for reasons that doctors have
not understood, after one or two years the
cancer cells are no longer vulnerable to
the drugs and begin growing again.
Typically, doctors remove the patients
from the anti-androgen, and patients
improve temporarily before the cancer
takes over again.
In 1998 Chang discovered
the first molecular evidence of just how
such drugs can actually spur prostate
cancer cells to grow under certain
conditions.
Yi-Fen Lee, Ph.D., now an
assistant professor in the Department of
Urology, began working with Chang to see
exactly how the switch takes place. Lee
studied cancer cells from four men,
comparing the cells from early in their
disease to their cells after hormonal
therapy became ineffective. The team,
which included Lee, Chang, and graduate
student Wen-Jye Lin, found a molecule
known as MAP kinase at much higher levels
in the cells that had survived hormone
therapy.
Then Chang and Lee found
that, in addition to cutting off
testosterone by targeting a protein known
as the androgen receptor, the
anti-androgen also turns on MAP kinase - a
molecule with promotes cell growth and is
known to play a role in diseases like
breast and prostate cancer.
The finding explains at
least part of the reason why drugs like
hydroxyflutamide, the anti-androgen the
team studied in the Cancer Research paper,
suddenly switch from being effective to
being ineffective. It's a surprise, the
scientists say, that the compound triggers
molecular signals that don't involve the
androgen receptor, which has long been the
main target of prostate cancer drug
treatments.
"In all of the more than
30,000 men who die of prostate cancer each
year, the cancer cells have become capable
of growing even when we starve the cells
of testosterone," says Edward Messing,
M.D., professor and chair of urology, who
treats hundreds of men for prostate cancer
each year. "In each one of those men,
there's been a fundamental change, so that
the molecule we've targeted for stopping
the cancer is no longer involved in the
disease. It's at this point that the
disease becomes a killer. Finding an
additional potential target for preventing
this switch is surprising and
significant."
Despite the drawbacks, the
scientists stress that current treatment,
including hormonal therapy, is currently
the best option for patients whose cancer
has spread beyond the prostate gland.
"These drugs are necessary
for patients who otherwise have few
options." Says Lee. "However, these
findings do raise some concerns that
should be investigated further. Perhaps
these findings will help lead to a new
drug target so that men with this disease
can be treated more effectively."
Working on the project
besides Chang, Lee, Lin, and Messing were
Jiaoti Huang, Ph.D., assistant professor
of pathology and laboratory medicine;
Franky Chan of the University of Hong
Kong; and medical oncologist George
Wilding of the University of Wisconsin.
The research was funded by the National
Institutes of Health.
This story has been
adapted by Science Daily from a news
release issued by University of Rochester
Medical Center, November 2002.
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