Experimental Therapeutics: Freezing Cancer, Making it Sick, Slowing it Down

Ronald Rodriguez, left, and Shawn Lupold.

At the Brady, cuttingedge work is happening at every level of prostate cancer we can think of — prevention, treating early disease, containing disease that is likely to spread, and finally, attacking cancer that has indeed made the serious leap outside the prostate, to distant sites.

The scientists in the experimental therapeutics group at the Brady, led by Ron Rodriguez, M.D., Ph.D., are in the business of developing new weapons and — this is a tough call, in a scientific think tank abundant in creative investigators — what they’re doing is among the Brady’s most innovative work. “The last year has been particularly exciting for the experimental therapeutics group,” says Rodriguez.

“Simply put, we are trying to
give cancer a cold.”

Among their weapons currently in development: Adenoviral gene therapy “Simply put, we are attempting to give cancer a cold,” says Shawn E. Lupold, Ph.D., the Virginia and Warren Schwerin Scholar, “by redirecting a common cold virus called adenovirus to selectively kill prostate cancer cells.” One challenge Lupold and Rodriguez have faced is that the androgen receptor, a gene often active in prostate cancer, “actually inhibits our therapeutic viruses, making them less effective,” Lupold adds. The team came up with a clever molecular engineering strategy to reverse this — “so the virus can team up with the androgen receptor, rather than compete with it.” These results were published in Molecular Therapy.

Another challenge has been to make the adenovirus more effective. As soon as a virus — even a helpful one — is detected in the body, the immune system begins fighting it. Thus, the best hope is for the virus to be so targeted that it zooms right to the desired cells (in this case, prostate cancer, wherever it may be hiding throughout the body). The quicker the virus starts to work, the longer the cancer-killing window before the immune system finds the virus and shuts it down. Lupold and Rodriguez have been developing new tools to improve the adenovirus’s ability to single out metastatic prostate cancer. “More than 90 percent of adenoviruses are absorbed by the liver and spleen soon after they enter the blood stream,” notes Rodriguez, “leaving only a fraction of the desired therapeutic dose for the cancer cells.” The current state-of-theart methods for altering adenovirus are slow and cumbersome, he continues.

“But recently, we have made significant inroads by generating a new technology, which allows us to make thousands or even millions of different viruses with various targeting features at the same time.” Using a technique known as “biopanning,” the scientists can screen these adenoviral libraries to identify viruses with the best ability to target and infect prostate cancer cells, but avoid other cell types, such as liver cells.

New use for an old drug Valproic acid is an anti-seizure drug that has been around for years. But recently, Rodriguez has discovered that valproic acid suppresses more than seizures — it also slows down the growth of prostate cancer. Even better, this happens at doses that have long been proven safe. “We believe that valproic acid causes a subset of cells to become less aggressive,” says Rodriguez. “In men who are already on hormonal therapy, this may delay the progression to androgen-independent disease.” Rodriguez and colleagues are testing valproic acid in a limited clinical trial, in men with a rise in PSA after hormonal therapy.

Not cryotherapy—immunocryotherapy “Cryo” means freezing. “Immunotherapy” involves strengthening the immune system, to help the body fight off cancer. Put them together, and you have immunocryotherapy. Why freeze prostate cancer? “So far, tumor vaccine therapy (immunizing the body against its own cancer) has met with very limited success,” explains Rodriguez. “We believe that one reason for this is that some cancers promote tolerance. Breaking tolerance has therefore become the ‘Holy Grail’ of cancer immunotherapeutics.” Rodriguez and colleagues including Moshe Levy, M.D., have been working on this for two years. They have developed a protocol for kidney cancer, and hope to start clinical trials soon for men with prostate cancer. “We freeze the prostate cancer at one site, while simultaneously stimulating the immune system with agents thought to inhibit the cells responsible for tolerance. Then we monitor the body’s anti-tumor immune response by studying prostate cancer at other sites that we have not treated.” This clinical trial will be open to men who have progressive, metastatic prostate cancer and still have an intact prostate.


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