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Senior Citizen Health & Medicine
Prostate Cancer Cells Killed by Protein Made by the
Cancer
Senior citizens with cancer or enlarged prostate
may be helped by discovery
November 10, 2006 Prostate cancer is high on the
radar for most older men, since it strikes about 680,000 in the world
every year and more than 220,000 die. Encouraging news, however, was
reported today that scientists have found a way of using a protein made
by prostate cancer to target and kill the cancer cells themselves.
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In preliminary studies the new therapy affected
only the prostate, without causing damage to other healthy tissues, and
now it is being tested in a phase I clinical trial.
Prostate cancer is one of the commonest cancers in
men. Furthermore, by the age of 80, approximately 80% of all men will
have developed a non-cancerous condition called benign prostatic
hyperplasia (BPH) in which the prostate gland becomes enlarged. The
findings reported today have the potential to improve the survival and
quality of life for men suffering from both these conditions.
Sam Denmeade, associate professor of oncology at
John Hopkins University, reported to the EORTC-NCI-AACR Symposium on
Molecular Targets and Cancer Therapeutics in Prague that he and his
team3 had developed a protoxin, named PRX302, by modifying an inactive
molecule, proaerolysin (PA). They engineered PRX302 to be activated by
prostate-specific antigen (PSA) a protein made in higher than normal
levels by prostate cancer. Once activated, they hoped that it would
target and kill prostate cancer cells specifically.
"This represents a different kind of 'targeted'
therapy, in that it seeks to use a protein made by the cancer to destroy
itself," he said.
Initial tests in the lab and in animals revealed
that when the protoxin was injected into cancerous prostate tissue, it
had a significant effect.
"In the lab, PRX302 produced significant and often
complete regression of the prostate cancer. Since the PSA gene is only
found in primates and humans, we then injected either 0.35 or 4.1
micrograms as a single 25 microlitre injection into PSA-producing
prostates of cynomolgus monkeys where it resulted in destruction of
either 25 or 50% of prostate tissue respectively.
This extensive damage was confined to the prostate
with no toxicity observed in any other normal tissues, including those
adjacent to the prostate such as the bladder, urethra, rectum and
seminal vesicles. Furthermore, two weeks after the injection, we saw a
disappearance of the toxin, but the continued presence of dead tissue,
suggesting that the toxin's effects could be long lasting.
"Our observations suggest that injections into the
prostate of this engineered, PSA-activated protoxin might have potential
in treating men with locally recurrent or advanced prostate cancer, or
for those with BPH where the protoxin could be used to reduce the size
of the enlarged prostate," said Professor Denmeade.
A phase I clinical trial is in progress now for men
with locally recurrent prostate cancer after definitive radiation
therapy."
At the moment, the therapy involves injecting the
protoxin directly into the prostate.
"As such, its application is limited to men with
recurrent disease after radiation who still have prostates. If it were
to work very well it might be used earlier, in combination with other
treatments, most likely radiation. In addition, the toxin is also under
consideration as treatment for BPH. We hope that we will be able to
further modify the toxin to make a systemic form that could be used to
treat advanced prostate cancer in the future."
The study is treating the third cohort of patients
and interim results are expected to be available at the end of the year.
PA is an inactive precursor of a bacterial protein
that kills cells by forming large pores in the cell membrane. PRX302
kills the cancer cells in the same way when activated by PSA.
The idea for this approach to treating prostate
cancer came when Prof Denmeade, who had been working on ways to harness
the activity of PSA with drugs, heard about PA.
"We called Dr Buckley, who is the world expert on
PA, and discussed our strategy. Within two weeks he had generated the
toxin and then we tested it for toxicities against a variety of cancers
in our lab before starting our studies in prostate cancer," he said.
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