| When prostate cancer
becomes advanced, its cells change. They go from being "well - differentiated,"
having clear borders, and well-defined shapes, to being more runny
— morphing into little, malignant blobs. Over the last decade,
scientists have been studying drugs called "differentiating agents"
that can help reverse this process — restoring shape and definition
to cancer cells, and slowing down their rate of growth.
"In the past, scientists have focused
predominantly on short-term treatment with these agents, looking
for rapid changes in tumor regression," explains urologist Ronald
Rodriguez, M.D., Ph.D., who is also an expert in molecular biology
and viral oncology. But short-term studies of these drugs have been
disappointing. He believes that giving differentiating agents to
a man who already has advanced cancer, and hoping for a quick turnaround,
is not the best way to approach these drugs. "Recently, we have
discovered that if these agents are given over long periods of time,
the effect on tumor progression can be profound," he says.
Even more exciting: Giving the drugs
chronically may even take the most hardened, difficult-to-kill cancer
cells - the ones called "androgen-independent," which no longer
depend on hormones and can't be killed by hormonal therapy - and
make them more vulnerable. "This appears to sensitize certain types
of androgen-independent cancer cells, converting them back into
androgen-dependent cells," says Rodriguez. "These findings may have
the most significant impact on men who develop a PSA recurrence
after radical prostatectomy." He and colleagues are now working
to develop clinical studies based on their most recent data, published
in the journal, Cancer Research.
“If
these agents are given over
long periods of time, the effect
can be profound.”
Lethal viruses: In 1997, Rodriguez
and colleagues were the first to harness a common cold virus, called
the adenovirus, as a weapon specifically designed to kill prostate
cancer cells. The adenovirus normally kills any cell it invades;
the trick of gene therapy was to make this an "oncolytic" virus—to
get it to target and invade cancer cells. Working with this virus
was one of the toughest challenges Rodriguez has ever wrestled with,
but he eventually engineered the adenovirus so that it would only
detonate when it came in contact with prostate cells. "This had
significant clinical activity when we injected it directly into
the prostate of patients who failed radiation therapy," he notes.
"But the real need is in men with advanced disease — and for
these men, direct injection is not an option." They tried injecting
the viruses intravenously, and had to face two enemies — prostate
cancer, and the patients' livers. The liver's job is to filter out
chemicals that appear harmful. "Despite the fact that greater than
99 percent of the viruses injected this way were sequestered in
the liver, we were still able to demonstrate clinical activity."
This work was published recently in Molecular Therapy.
To overcome this obstacle, they worked
to make the virus — what little of it could make it past the
liver — even more potent. Rodriguez and colleagues also have
developed a means to bypass the liver, and "get much more of the
virus to the prostate cancer cells." Those efforts are being led
by scientist Shawn Lupold, Ph.D. Eventually, Rodriguez believes,
"with these new developments, we will be able to have a significant
impact on the patients with the greatest need — men with advanced
prostate cancer.”
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