A Publication of the James Buchanan Brady Urological Institute Johns Hopkins Medical Institutions




Ted De Weese and Ron Rodriguez:
Testing a doctored version of a common cold virus, programmed to detonate only where it finds PSA.

If prostate cancer has a saving grace, maybe it's PSA. This enzyme, found in the bloodstream, is an indispensable tool in diagnosing the disease and deciding treatment.

Scientists studying cancers elsewhere in the body -- in the breast, the colon, or the brain, for instance -- would give their eye teeth for a potential weapon as selective as this: Nearly every prostate cell makes PSA, which stands for prostate-specific antigen. The very fact that it is prostate-specific means no other cells need be harmed by a new kind of genetically engineered drug, designed at Hopkins, that enters the body "locked and loaded," in effect, and ready to fire at PSA's signal.

It's a marker for every stage of prostate cancer, and even a predictor of its course. It is also an excellent target for new chemical warfare so precise that it can be taught to seek out and destroy only the cells that make PSA.

The drug is a "smart bomb" that uses a doctored version of a common cold virus called an adenovirus, programmed to detonate only where it finds PSA. "We're trying to give prostate cancer a lethal common cold, but leave all the normal cells alone" says oncologist Jonathan Simons, M.D. He and Ron Rodriguez, M.D., Ph.D., a urologist with expertise in genetic engineering and cell biology, developed the PSA-targeted virus a couple of years ago, and have shown exciting results in animal studies: In fact, using "nude" mice (which have no immune system, and thus can grow human tumors), Rodriguez was able to obliterate one-centimeter-sized tumors -- which are propotionally huge--within six weeks, after a single injection.

Those promising results, published in the journal Cancer Research in 1997, were the basis for the first adenoviral gene therapy trial, now nearly completed, in men who had a local recurrence of prostate cancer after radiation treatment, detected by a rise in PSA. One reason the scientists picked this group of men was that -- unlike radical Prostatectomy patients -- they still have a prostate, which can be biopsied as a means of measuring the drug's success. Another, explains radiation oncologist Ted DeWeese, M.D., who with Simons led the trial is that "these men are otherwise generally healthy, and right now there's nothing else we can do for them," except to begin hormonal therapy months or years later, if the men develop symptoms of advanced prostate cancer. "It's obviously very anxiety-provoking to watch your PSA going up, and we'd like to look for something that could potentially cure them." (The men in this trial can still receive hormone therapy, if it becomes necessary.)

This was a Phase I trial, designed simply to make sure a drug is safe for patients to take -- not to measure any other results, such as changes found in PSA levels or biopsies. Nonetheless, "we've certainly seen some exciting things," says DeWeese. "We're excited by how easily tolerated it is in patients, with minimal side effects. We've also seen changes in PSA that we hope to follow up on in our Phase II study." Adds Rodriguez: "Several men have had significant declines in their PSA. Even in the ones who didn't -- most of them have not had the increase in PSA that you would have expected." (For more on the rise of PSA after treatment, see What Happens if PSA Comes Back After Surgery

DeWeese administered the virus using a highly accurate computer program he helped design a year ago to administer brachytherapy seeds -- in fact, the technique is similar, except that instead of radioactive seeds, it's droplets of virus being placed with exquisite precision within the prostate, guided by transrectal ultrasound and a three-dimensional, CT scan image of the prostate. DeWeese injected the virus directly into the prostate because he, Simons and Rodriguez believe it's the best means of buying more time for the virus to work -- before the body's immune system spots the invader and attempts to knock it out. "We've all been exposed thousands of times to the common cold virus, " DeWeese says. "Most of us have antibodies primed and ready to strike, to mount an immune response. So while all of these patients will get an immune response at some point, at least it's delayed long enough to allow some replication of this virus, and therefore killing, to occur."

The investigators monitor the Virus's progress inside the prostate with biopsies, one at Day 4, and one at Day 22. One of the things the investigators hope to accomplish with this trial is to find out how much of the virus ultimately makes it out of the prostate and enters the bloodstream. They have attempted to answer this question by regularly scrutinizing the blood for the presence of antibodies to the virus -- or, as DeWeese puts it: "When does a patient's body start to notice that it's around?" And is there a window of opportunity -- if, say, in later studies scientists injected it intravenously -- when the virus could be used to reach a host of sites in the body? It may be that, if the virus demonstrates some staying-power in the bloodstream, it could help men with metastatic disease.

Another " very exciting" suggestion from this early study and from laboratory work is that the virus may be effective used even earlier -- "maybe with radiation up front", says Deweese, "to increase the amount of killing that radiation might provide. This would add another important weapon to our arsenal." The early study was a large collaborative effort, which also involved radiologist Ulrike Hamper, M.D., pharmacist Marti Goemanns, patient coordinator Renee Drew, and Calydon, the company that is producing the virus.

Where do we go from here? Ron Rodriguez, for his part, has continued to improve the virus, developing "son of" viruses -- second- and third-generation drugs -- and exploring different means of delivering them. This work has sparked a series of bold ideas and experiments: One of the most daring involves a powerful agent that Rodriguez admires for its ruthless, cell-killing efficiency -- the diphtheria toxin (DPT). "It's a very potent cellular toxin that poisons protein synthesis," he explains. "It's among the most potent molecules known to man: As little as one molecule of this toxin can kill a cell." Rodriguez is working to add this deadly cocktail to the mix. Already he has mastered the intricate feat of engineering diphtheria into the adenovirus.

"It's obviously very anxiety provoking to watch your PSA going up, and we'd like to look for something that could potentially cure them.

"I'm very excited about this DPT virus " says Rodriguez. "In fact, at the moment, it's too potent; I'm working on decreasing its total activity." Unlike other agents, the diphtheria-engineered virus does not rely on cell proliferation, or division, as an ignition switch. "The DPT toxin doesn't care about any of that. If you're a cell that's resting, and you get exposed to DPT, you're going to die." Rodriguez is also working with other prostate-specific sequences of DNA, called promoters, which he has cloned. Some of these, he notes, may turn out to be more responsive to hormones; others may work best in prostate cancer that does not respond to hormone therapy. "Advanced cancer," he explains, "is a different animal. " One day, if viruses designed with these promoters prove successful, "we may be able to custom-engineer a virus to fit patients' different needs."

Rodriguez et al. "Identification of Diphtheria Toxin Via Screening as a Potent Cell Cycle and p53 Independent Cytoxin for Human Prostate Cancer Therapeutics." Prostate, Vol.34, No. 4:259-269. 1998
Rodriguez and Simons. " Urologic Application of Gene Therapy." Urology. Vol. 54, No. 3:401-406. 1999 



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