October 2001

From Yale University

Yale researchers develop new molecule that eradicates cancer by destroying tumor blood vessels

Researchers at Yale have developed a new molecule they call "icon" that targets blood vessels in tumors for destruction by the immune system without harming vessels in normal tissues.

"Our study resulted in the eradication of injected tumors and also of other tumors in mice that had not been injected," said principal investigator Alan Garen, professor of molecular biophysics and biochemistry at Yale University. "This serves as a model of metastatic cancer. None of the normal tissues in the mouse appeared to be harmed by our procedure."

Published in the October 9 issue of Proceedings of the National Academy of Sciences, the study was conducted with human melanoma and prostate tumors growing in mice. The gene for the icon was inserted into an adenovirus vector that was injected into a tumor, resulting in the infection of tumor cells that act within the mice as factories for producing the icon and secreting it into the blood.

Garen said that in order to target tumor blood vessels without harming the normal blood vessels, a molecule that is expressed specifically on the inner surface of the tumor is needed. The molecule used for this study is called tissue factor, whose normal function is to initiate blood clotting.

Blood clotting occurs when another molecule called factor VII, which circulates constantly in the blood, binds to tissue factor. The binding of factor VII to tissue factor is one of the strongest and most specific interactions known in biology. Garen and Yale research scientist Zhiwei Hu, constructed the icon, which is modeled after a camel's version of an antibody. The icon is composed of two parts. One part targets the icon to tissue factor by using factor VII as the targeting domain. The other part of the icon is the region of a natural antibody that activates an attack by the immune system against cells that bind to the icon.

"The result is that the tumor blood vessels are destroyed by the immune system and consequently the tumor cells die because they lack a blood supply," said Garen. "The normal blood vessels survive because they do not express tissue factor and therefore do not bind the icon."

"This icon should work against all types of tumors that contain blood vessels," said Garen. "The icon that will be used in a clinical trial is derived entirely from human components and therefore should not be significantly immunogenic, which is an advantage over antibodies used in this kind of study."

Garen said the procedure could also be effective against other diseases that require growing blood vessels, such as macular degeneration, the major cause of blindness in older people.

A clinical trial is being arranged by Albert Deisseroth, M.D., formerly of Yale, and currently President of the Sidney Kimmel Cancer Center in San Diego.

The study was funded in part by the National Institutes of Health and by gifts from private donors.











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