JOURNAL OF CLINICAL INVESTIGATION EMBARGO: 5 p.m. (Eastern) Tuesday, July 1, 2003

Cancer Researchers Describe New Class of Angiogenesis Proteins

Researchers at the Rebecca and John Moores UCSD Cancer Center, and colleagues from throughout the state, describe a new class of proteins that not only promotes therapeutic angiogenesis in an entirely new way, but also avoids vascular permeability a troubling side effect seen with other agents now being tested.

Angiogenesis, the process by which the body forms new blood vessels, occurs in cancer, arthritis and other diseases, and in normal processes such as embryonic development, wound healing and ovulation. Researchers worldwide are working on ways to promote angiogenesis in the treatment of some diseases, such as heart disease and peripheral arterial disease (PAD), and to inhibit angiogenesis in others, such as cancer.

Judith Varner, Ph.D.

The research team, led by Judith Varner, Ph.D., associate adjunct professor of medicine at UCSD School of Medicine, reports its in vitro and animal study findings on the Del-1 protein in the July 1 issue of the Journal of Clinical Investigation.

Del-1, an extracellular matrix (ECM) protein, was discovered about four years ago by co-author Thomas Quertermous, M.D., of Stanford. In this paper the researchers describe its function, the mechanism by which it works, and its potential for human therapy. They have christened this new class of pro-angiogenesis factors "angiomatrix" proteins.

"Most of the pro-angiogenesis proteins we know of so far are growth factors, which are soluble, so they may disappear after a short time, and are often associated with side effects that can limit their clinical potential," said Varner. "Our data show that Del-1 is very stable, doesn't diffuse away, and has the potential ability to continually stimulate angiogenesis."

Varner added that Del-1 does not cause vascular permeability, or edema, a damaging condition in which the cells lining the blood vessels move apart from each other, allowing lymphocytes and other cells to enter tissues and release their oxidants.

In animal studies the researchers compared Del-1 to one of the leading growth factors now being tested vascular endothelial growth factor (VEGF).

"In our testing in animal models of ischemia, the two agents were similar in their ability to stimulate angiogenesis and improve muscle function, but there were no side effects with the Del-1 therapy, unlike with VEGF," she said.

These same findings have been borne out in a recently completed Phase I clinical trial of Del-1 sponsored by Valentis, Inc. of Burlingame, CA. The company announced June 9 at the 6th Annual Meeting of the American Society of Gene Therapy in Washington, D.C., that its lead product, a Del-1 drug for the treatment of PAD was well tolerated at all doses tested and there were no serious side effects seen. While the Phase I study was designed to test safety, the company reports evidence of dose-related activity. Based on the trial results, Valentis is planning a Phase II trial to begin soon.

Varner has been studying Del-1 since it was discovered. Initially she found that it promoted migration and survival of endothelial cells through an adhesion receptor called alpha-v-beta-3. She knew a piece of the puzzle was missing, however, because that receptor is not expressed on normal blood vessels, only vessels already undergoing angiogenesis.

"We didn't know how Del-1 actually initiated angiogenesis until we found another receptor, the alpha-v-beta-5, that's further upstream in the process," she said. "You absolutely need that receptor to develop angiogenesis in response to the Del-1 protein."

Varner's team found that Del-1 initiates angiogenesis by locking onto the cell membrane using the alpha-v-beta-5 cell adhesion receptor. Once tethered it activates a powerful transcription factor called Hox D3. The transcription factor launches a cascade of events that changes the profile of the cell, making it angiogenic. Later in the process, Del-1 interacts with the alpha-v-beta-3 receptor to promote migration and survival of the endothelial cell.

While this paper explored Del-1's pro-angiogenic role in ischemia, Varner said, she and co-author Quertermous have also studied its expression and function in cancer. Del-1 is expressed and promotes angiogenesis in many tumors.

"In the cancer setting, you want to inhibit angiogenesis," she said. "Knowing the mechanism will help us design therapies that can inhibit Del-1."

Besides Varner, co-authors are Jingping Zhong, Ph.D., Department of Medicine and Moores UCSD Cancer Center; Brian Eliceiri, Ph.D., and Dwayne Stupack, Ph.D., of the Department of Immunology, The Scripps Research Institute, La Jolla; Kalyani Penta, Ph.D., Gordon Sakamoto, M.D., and Thomas Quertermous, M.D., all of the Donald W. Reynolds Cardiovascular Clinical Research Center, Stanford University; Mike Coleman, Ph.D., of Valentis Inc.; and Nancy Boudreau, Ph.D., of the Surgical Research Laboratories, University of California, San Francisco.

This work was supported by grants from the National Cancer Institute, and the National Heart, Lung and Blood Institute.

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