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Release: Dec. 17, 2002

UI cancer researchers receive grants to 'translate' findings into applications

Two University of Iowa researchers have received Translational Development and Clinical Trials Seed Grants for prostate cancer and breast cancer investigations. The one-year, $10,000 awards were made Dec. 1 through the Holden Comprehensive Cancer Center at the UI.

These awards help faculty develop translational projects, which are investigations that involve transferring basic research findings into practical applications that may be tested through clinical trials.

Thomas Griffith, Ph.D., UI assistant professor of urology, received support to investigate a gene-transfer approach as a potential alternative to the invasive surgery that many prostate cancer patients currently receive as treatment. Susan Roman, D.O., UI assistant professor of internal medicine, was awarded support for the investigation of a drug combination treatment for patients with advanced breast cancer.

Griffith's study aims to introduce a gene into prostate tumor cells so that they will die off through a natural process known as apoptosis. The specific gene is TNF-related apoptosis inducing ligand (known as TRAIL/Apo-2L), and it signals, or "turns on," apoptosis. An adenovirus, which is a disabled viral delivery vector, would be used to deliver the gene into targeted cancer cells.

In preliminary tests, TRAIL/Apo-2L caused a variety of tumor types to die, yet did not harm normal tissues. The gene also is known to suppress tumor growth through apoptosis in mice that have been implanted with human tumors.

Griffith and colleagues then found similar effects by introducing the gene into prostate tumor cells and normal prostate cells in tissue cultures and animal models. The UI Gene Transfer Vector Core contributed to the effort by producing the TRAIL/Apo-2L–containing adenovirus.

Griffith's team now will test this laboratory-grade vector when it is combined with other prostate cancer treatments such as chemotherapy and immunotherapeutic strategies. The study will be done in tissue cultures and animal models.

The next step for the researchers then will be to evaluate the gene therapy in patients, once institutional and federal approval is given for a clinical study. That investigation will use a clinical-grade vector produced by a company in California.

"Everything we have done so far in the lab has been designed to move this particular vector into the clinic and test it in men with prostate cancer," Griffith said. "We will then see if we get the same kind of activity in people that we get in the animal models, which is the destruction of tumor cells. We also hope that the dead tumor cells will help activate the immune system and initiate an anti-tumor response."

Roman's study will investigate the combination of docetaxel, a chemotherapy drug, and lovastatin, a blood cholesterol–lowering drug, as a potential treatment for advanced breast cancer.

"Docetaxel, which is also known as Taxotere, is one of the most effective drugs in the treatment of advanced breast cancer. Unfortunately, not all patients treated with this drug will have a shrinkage in their tumor, or the response may be short-lived," Roman said.

Roman and colleagues hypothesize that the addition of lovastatin may strengthen the effects of docetaxel without adding many harmful side effects. Advanced breast cancer is a cancer that has spread (metastasized) and is difficult to treat or has recurred but cannot be treated surgically or by other means.

The study builds on research undertaken by Roman and co-workers since she joined the UI faculty earlier this year. Sarah Holstein, a student in the UI Medical Scientist Training Program, previously demonstrated that lovastatin adds to the anticancer activity of paclitaxel (Taxol), a drug that is related to docetaxel. Holstein works with Raymond Hohl, M.D., Ph.D., UI professor of internal medicine and pharmacology.

"Together, lovastatin and paclitaxel are more effective than either drug alone, resulting in increased cancer cell death," Roman said. "Similarly, we will now see if lovastatin will enhance the effects of docetaxel, which has already been shown to be a very effective drug in treating patients with advanced breast cancer. My laboratory data indicate that we will see synergism in people."

Part of Roman's investigation, which uses human-derived breast cancer cells, will be to study how the two drugs actually work together to inhibit breast cancer cell growth.

Roman's team plans to open a clinical trial within the next months that would target women with advanced breast cancer. The first part would investigate the safety of the drug combination for patients with any type of solid tumor. The second part would investigate optimal doses in women with advanced breast cancer.

"The beauty of the clinical trial is that we would use two drugs already in clinical use, and that the addition of lovastatin to docetaxel may result in few, if any, additional side effects," Roman said. "The hope is that we are going to improve the anticancer effects of docetaxel without adding harmful effects to the patient."

Griffith, Hohl and Roman are members of the Holden Comprehensive Cancer Center at the UI, which is Iowa's only National Cancer Institute (NCI)-designated comprehensive cancer center. NCI-designated comprehensive cancer centers are recognized as the leaders in developing new approaches to cancer prevention and cancer care, conducting leading edge research and educating the public about cancer. Visit the center online at www.uihealthcare.com/depts/cancercenter