Scientists design a PSA-activated protoxin that kills prostate cancer

Nov 10, 2006

Scientists have found a way of using a protein made by prostate cancer to target and kill the cancer cells themselves. 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, with nearly 680,000 new cases each year worldwide and more than 220,000 deaths. 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 (Friday 10 November) 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, USA, 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.

He explained: "This represents a different kind of 'targeted' therapy, in that it seeks to use a protein made by the cancer to destroy itself."

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 for some time 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."

Source: European Organisation for Research and Treatment of Cancer

Explore further: Study shows how breast cancer cells break free to spread in the body

add to favorites email to friend print save as pdf

Related Stories

Protections blocked, but sage grouse work goes on

34 minutes ago

(AP)—U.S. wildlife officials will decide next year whether a wide-ranging Western bird species needs protections even though Congress has blocked such protections from taking effect, Interior Secretary Sally Jewell said ...

Sprint accused of billing for unwanted services

44 minutes ago

(AP)—Federal regulators are accusing Sprint Corp. of illegally billing its wireless customers tens of millions of dollars in unwanted charges for text message alerts and other services.

Short-necked Triassic marine reptile discovered in China

46 minutes ago

A new species of short-necked marine reptile from the Triassic period has been discovered in China, according to a study published December 17, 2014 in the open-access journal PLOS ONE by Xiao-hong Chen f ...

Recommended for you

Researcher to cancer: 'Resistance will be futile'

4 hours ago

Turning the tables, Katherine Borden at the University of Montreal's Institute for Research in Immunology and Cancer (IRIC) has evoked Star Trek's Borg in her fight against the disease. "Cancer cells rapidly ...

How does prostate cancer form?

6 hours ago

Prostate cancer affects more than 23,000 men this year in the USA however the individual genes that initiate prostate cancer formation are poorly understood. Finding an enzyme that regulates this process ...

Low risk of malignancy for small complex adnexal masses

13 hours ago

(HealthDay)—For older women with small complex adnexal masses, the overall risk of malignancy is low, according to a study published in the December issue of the American Journal of Obstetrics & Gynecology.

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.