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.
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