Researchers have created transgenic mice that express human prostate-specific antigen (PSA) almost exclusively in their prostates, exactly like human males, providing scientists with the best animal model yet in their search for a more effective treatment for prostate cancer. Scientists expect the mice will speed up research on prostate cancer by providing a less expensive means to test potential new treatments. The team from the University of Rochester Cancer Center reports its work with the transgenic mice in the June 10 issue of the Proceedings of the National Academy of Sciences.
The team also demonstrated the first step toward a tumor vaccine for prostate cancer. The scientists were able to provoke an immune response in the mice, compelling the mice to attack their own cells that contained PSA, but not their other cells. Marshaling the immune system to attack a tumor more vigorously and more specifically than any drug can is known as immunotherapy, and it's currently being tested as a treatment for melanoma. A tumor vaccine that recognizes PSA-containing cells would have the advantage of targeting not only prostate cells but also metastases from prostate cancer anywhere in the body.
"Creating a mouse that can make killer T cells against PSA suggests that a tumor vaccine is very possible," says lead author John Frelinger, associate professor in the University's Cancer Center. "The biggest obstacle to creating a vaccine has been the lack of a mouse model to study vaccines in detail. The mice we have created mimic human PSA expression exactly -- they're ideal for studying potential treatments for prostate cancer."
A tumor vaccine that targets PSA-containing cells would solve the biggest problem doctors have in treating the disease: Most patients die not from the primary tumor, but from metastases to other organs, such as the bones or lungs. Currently physicians rely mainly on surgery and radiation to treat the disease, which afflicts 200,000 men in the U.S. each year and is the second- leading cause of cancer deaths among American men. Those treatments often work well as long as the cancer hasn't spread to other parts of the body; currently there is no way to target cancer cells that have spread from the prostate, so chemotherapy is rarely an option.
Like most of our genes, the PSA gene is present in all cells in a man's body but is turned on only in certain cells -- in the case of PSA, it's made almost exclusively in the prostate. Scientists created the mice by putting into them not only the human PSA structural gene but also a large piece of DNA surrounding it; the scientists found that this extra DNA contains the instructions responsible for turning on the PSA gene in the prostate.
In theory this tissue-specific "on" switch offers a way to express genes only in prostate cells. Doctors someday hope to be able to pick a gene that makes cells susceptible to a drug, introduce the gene into a patient, then turn it on only in certain cells, such as tumor cells derived from the prostate. Such specific expression is exactly what the team did with the mice and the human PSA gene.
Frelinger's colleagues in the research included post- doctoral associate Chungwen Wei, graduate student Richard Willis, technician Brian Tilton, and faculty members John Looney, Edith Lord, and Richard Barth.
"This project has been a joint effort -- a nice marriage of people's interests," says Frelinger. "Any one of us could have conceived of this project, but no single one of us could have pulled it off. Dr. Lord's interest in immune response to tumors, Dr. Barth's expertise with transgenic mice, and Dr. Looney's knowledge of auto-immunity all were vital to this work."
The project was supported by the National Institutes of Health, the Rochester Area Pepper Center, the American Cancer Society, and the Sally Edelman and Harry Gardner Cancer Research Foundation of Hilton, a local group that has raised approximately $250,000 for University researchers studying ways to stop cancer.
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