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.