PSA has long been used as a monitor, a marker, and
a detector. Now, thanks to two Brady researchers, PSA has a new job —
as a trigger, a detonator of a “smart bomb”designed to kill
locally advanced prostate cancer.
This work takes advantage of PSA’s normal role in the body as an
enzyme that, like a pair of “molecular scissors,” cuts other
proteins into small pieces, says John Isaacs, Ph.D., professor of urology,
who developed this new therapy with Samuel R. Denmeade, M.D., associate
professor of oncology.
Working together with scientist Thomas Buckley, from the University of
Victoria in British Columbia, Isaacs and Denmeade have modified a highly
potent bacterialtoxin called aerolysin — which comes from a Mediterranean
plant called Thapsia garganica (known as the “death carrot”).
In its altered form, however, aerolysin’skilling powers are severely
limited: It’s onlytoxic in the presence of PSA. “The treatmentis
highly focused,” Isaacs explains. “PSA is only made by normal
prostate and prostate cancer cells, and it only functions as molecular
scissors within cancerous tissue — notin the blood stream. This
means that it will only target and kill prostate cancer cells, and leave
normal tissues alone.”
PSA detonates aerolysin by snipping off its tail — which allows
the toxin to drill large holes in the cell membrane. These holes cause
the cell to swell, and then explode. Isaacs and Denmeade have testedtheir
PSA-detonated bomb in mice that have human prostate cancer, with exciting
results: Just one injection of the toxin into the center of the tumor
leads to a dramatic reduction in tumor size. In one recently completed
study, 60 percent of mice receiving a single injection had no detectable
tumor 15 days after the treatment.
Denmeade and Isaacs are developing this therapy with Protox Therapeutics,
Inc., for injection into the prostate gland in men with prostate cancer
that has returned after radiation therapy. In toxicology studies required
by the FDA before the drug can betested in humans, a single injection
of thePSA-detonated toxin into the prostate of monkeys (the only other
species besides humans that makes PSA) produced wide-spread destruction
of prostate tissue without any significant side effects. Once these toxicology
studies are completed, the first clinical studies in men with recurrent
loca-ized prostate cancer will be performed at Johns Hopkins by Ted Deweese,
M.D., chairman of radiation oncology and molecular radiation science.
These clinical trials are expected to begin in early 2006.