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Release: Jan. 19, 2000

UI Cancer Center researchers receive American Cancer Society grants

IOWA CITY, Iowa -- Good research begins with good ideas. Faculty members at the University of Iowa Cancer Center have both. Three researchers have been selected as recipients in the first round of American Cancer Society (ACS) Seed Grants for 1999-2000. The grants allow junior faculty members and scientists to pursue new projects and make further progress in studying the cause, prevention and treatment of cancer.

The UI recipients include Thomas S. Griffith, Ph.D., associate in urology; Aloysius J. Klingelhutz, Ph.D., assistant professor in microbiology; and Emil Racila, M.D., assistant research scientist in the UI Cancer Center. Each grant recipient has received $20,000, which will fund their projects for the year.

Griffith's research, "Adenoviral Delivery of the Gene for the Apoptosis-Inducing Cytokine, TRAIL, as a Therapy for Prostate Cancer," will focus on developing an approach to introduce a specific gene into prostate tumor cells, so they will die off through a natural process known as apoptosis. Apoptosis is a biological occurrence in which the death of a cell is genetically and biochemically regulated.

"Most of the molecules essential for apoptosis are already present in a non-active form just waiting for a sign to initiate a self-destruction program," Griffith said. "In other words, cells appear to sense that their presence is undesirable to the body as a whole, whereby they silently commit suicide and are swiftly cleared by their neighbors."

The gene TRAIL (TNF-related apoptosis inducing ligand), identified as a member of the tumor necrosis factor family, signals the death program in cells. In preliminary tests, TRAIL was toxic against a variety of tumor types and nontoxic to normal tissues. It has also been discovered that TRAIL can suppress tumor growth through the apoptosis mechanism in mice that have been implanted with human tumors.

With these promising results, the next step in Griffith's work is to develop an adenovirus containing the human TRAIL gene and examine the effects it has on prostate tumor cells and normal prostate cells upon infection in culture or when growing in an animal. The UI Gene Transfer Vector Core is contributing to the effort by producing a TRAIL-containing adenovirus.

"It is the hope that these studies will demonstrate that this viral-based method of gene therapy will effectively deliver the TRAIL gene, and the resulting protein product will cause the prostate tumor cells to commit suicide," Griffith said.

Griffith said that the appeal of this study is that it may introduce a new therapy that can be combined with other prostate cancer treatment protocols to enhance the activity of the TRAIL produced. In addition, using this procedure is an alternative to invasive surgery, which many prostate cancer patients undergo for treatment.

Understanding cell death and the role it plays in cancer is also key to the work of Aloysius Klingelhutz, whose project is titled, "Identification of Genes Involved in Keratinocyte Senescence."

Klingelhutz explained that normal human cells die after a certain number of cell divisions, while cancer cells divide indefinitely and are considered "immortal." Senescence is the process of regulated cell death, and it is believed to play a significant part in preventing normal cells from turning into cancer cells. Cancer cells retain their enduring properties by alternating DNA; they do this specifically in genes that are involved in senescence.

"The goal of the project is to identify and focus on those genes that are involved in the senescence of human epithelial cells," Kingelhutz said. "Over 90 percent of human cancers arise from epithelial cells, so learning more about how these cells become immortal has the potential of leading to better prevention, diagnosis and treatment of a number of different cancer types."

The UI research team working on the project will use state-of-the-art technology known as cDNA microarray expression analysis, available through the UI DNA Facility. With this tool, researchers can examine the expression patterns of thousands of genes at one time.

Emil Racila is also employing new research techniques for his project, "Detection and Characterization of Carcinoma Cells in the Blood of Patients with Breast Cancer."

The research begins with the hypothesis that cancer cells enter the blood of most patients at an early stage in tumor development. In previous studies, patients with various stages of breast cancer have had carcinoma cells appear in their blood. According to statistical analyses, between 13 and 35 percent of women with localized, no-spread breast cancer will have a recurrence and die from their disease, even after primary tumors have been removed.

"This suggests that distant micrometastases have been missed in some of these patients," Racila said. "The need for a more sensitive method for evaluating the spread of carcinoma is evident."

Cancer spreads through the blood and lymph nodes. By utilizing techniques to detect and characterize carcinoma cells in peripheral blood, researchers are hoping to identify cancer in its early stages, when treatment is easier and more effective.

The test involves a magnetic bead approach, in which epithelial cells are selected. Epithelial cells form in the skin, glands and other tissues, and are not found in the bloodstream. Blood from the patient is mixed with a colloidal suspension of very small iron particles that are coated with antibodies specific for epithelial cells. Magnets are then used to separate and evaluate the epithelial cells.

While the central focus of the project is on breast cancer, Racila and his team will also look at the detection of adenocarcinoma cells from primary tumors in other organs and melanomas as well.

Racila said the benefit of this research is to treat early-stage tumors and aim for a higher survival rate. Through tests such as this, Racila hopes that more physicians can monitor the metastatic development of breast cancer and pass on valuable information to patients when they make decisions about treatment options and participating in clinical trials.

The UI Cancer Center in Iowa City is dedicated to cancer research, clinical care, education, detection and prevention. The center advances cancer research and education through the collaborative efforts of researchers and physicians from 26 departments in six UI colleges and the UI Hospitals and Clinics. Using knowledge gained through this research, UI physicians and other health care professionals work together in the John and Mary Pappajohn Clinical Cancer Center to provide the most advanced cancer care available in a manner that recognizes each patient as an individual.

University of Iowa Health Care describes the partnership between the UI College of Medicine and the UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide.