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BCM SPORE takes on high-risk research hoping for greater benefit

by Ruth SoRelle, MPH

Timothy Thompson, PhD

Baylor College of Medicine's federally funded Specialized Program of Research Excellence (SPORE) in prostate cancer was not designed to be a safe place where researchers narrowly followed the paths trodden by science before. Its director, Timothy C. Thompson, PhD, makes no apologies for that.

"We are doing high impact, high risk research in terms of benefit," said the BCM professor in the departments of urology, radiology, and molecular and cellular biology. "That's what goes on in this program. The prostate program is known for trying to hit a home run."

That takes on new meaning in the area of prostate cancer. There are few drugs or treatments for prostate cancer once it has spread beyond the boundaries or capsule of the prostate gland itself, he said.

"Breast cancer has a lot of drugs that are used in metastatic disease," said Thompson. "Prostate cancer is not in that arena. The drugs that exist have minimal impact."

A different tack

Thompson and his SPORE colleagues are taking a different tack. Instead of looking for more drugs, they are focusing on the biology. That means introducing a gene or protein into a tumor or a person's body in hopes that it will seek out the prostate cancer and destroy it.

Compared to other institutions, BCM's history in the field is long. In 1996, scientists and physicians teamed up to provide the first gene therapy in prostate cancer. That therapy, which teamed a gene for a herpes simplex virus enzyme called thymidine kinase with a cell-killing drug called ganciclovir, was only minimally successful, Thompson said, but it started the College down the road to better gene or protein therapies. He and his colleagues knew they could build on that experience and deliver one that was even better.

Today, the College has embarked on a study using IL-12, an immune-system protein that is attached to a weakened adenovirus (usually associated with respiratory illnesses). The study is being carried out under the leadership of Brian Miles, MD, professor of urology at BCM. The special gene-virus combination is injected directly into the prostate gland itself. There IL-12 begins to attract immune system cells called natural killers that attack the tumor cells themselves.

The death of the tumor cells releases tumor antigen into the system and that stimulates cell-killing T-cells of the immune system to attack anywhere they see the markers that tell them a tumor is present.

New study

On track for tests in the near future is a study that combines IL-12 and radiation. In animal studies, the two seem to create a synergy so that treatment with both is more potent and has wider-ranging effects than treatment with either one alone, said Thompson.

"It's doing a lot of interesting things biologically," he said. "The radiation seems to potentiate the immune cell activation mechanism of IL-12." It also causes release of molecules that encourage tumor cell death (through a mechanism called apoptosis).

Currently, Thompson and his colleagues are trying to find out which molecules are being activated by both IL-12 and radiation.

"This result means that we can add IL-12 to a common therapy - radiation - and potentially get benefits of both and this interesting synergy they cause. They affect not only the primary tumor but also metastatic disease (disease spread beyond the prostate) in animal models."

He and his colleagues think this is the result of a systemic anti-tumor response that can not only kill the original tumor cells but also those that are disseminated throughout the body.

As soon as the first phase of the IL-12 alone trials are done, Thompson hopes that studies that involve radiation and IL-12 can begin, in cooperation with Brian Butler, MD, BCM professor of radiology, and Bin Sing Teh, associate professor of radiology at BCM.

Better things

"This is a bridge to better things that have been coming on track in the lab for the past five to seven years," said Thompson.

One of those better things began with the identification of a gene that normally protects against tumor cells in the body. In prostate cancer, the protein RTVP-1 is trapped in epithelial cells (cells of skin and others tissues that line the exterior and interior of the body). Even when cancer is developing inside the prostate tumor, the cancer fighting protein cannot act. Once the cancer escapes the prostate gland itself, however, RTVP-1 moves into action, killing the tumor cells in the immediate area. Not only that, but it makes it possible for other potent immune-system cells called the dendritic cells to begin their siren call that attracts the immune system's killers to act against the tumor.

"No other protein has been identified that does that," he said. "We feel we have a major molecule involved in immunosurveillance."

He wants to capitalize on that protein's normal function and use it to attack spreading prostate cancer. One way would be to attach the gene to a virus and attempt gene therapy directly in the tumor itself. Plans for that are already underway. Another potential way to deal with it is to use the protein associated with RTVP-1 as a treatment. It would be easier to use and lack the problems associated with using a virus to take a gene into cells, said Thompson.

Work such as that done in the prostate SPORE and the other BCM SPORE that deal with breast cancer have bridged a gap between bench scientists who work in a laboratory and physicians, who care for patients, said Thompson.

"People in the basic and clinical sciences are working together," he said. "People in the basic sciences are conversant with and understand clinical questions and problems. And vice versa. This is very novel. It doesn't happen in the typical industry-based clinical trial system."

It benefits everyone, and particularly the patients, said Thompson.

"They are able to access therapies that might not be developed by drug companies," he said. "People can get involved in phase I or II drug trials that can have a positive impact on their disease."

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