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Molecule that targets tissue factor is found to thwart tumors in mice

Yale researchers have developed a molecule that, when injected into tumors in mice, destroyed blood vessels in tumors and left normal tissue unharmed. Their findings, published in the October 9 issue of Proceedings of the National Academy of Sciences, hold the promise of a new therapy for metastatic cancer.

The molecule, developed by Alan Garen, Ph.D., and Zhiwei Hu, Ph.D., in the Department of Molecular Biophysics and Biochemistry, is an immunoconjugate, or icon, which joins elements of different molecules. The team’s strategy—targeting a tumor’s blood vessels without harming normal cells—led them to the molecule tissue factor (TF), which is expressed on the inner surface of the tumor blood vessels and initiates blood clotting.

Garen and Hu’s icon is made up of two elements, one that draws it to TF and another that initiates an immune response. The first element is factor VII, a molecule that circulates in the blood and binds to TF. Once factor VII has drawn the icon to TF in the tumor, the icon triggers its second element, the Fc region of a human antibody, which activates the immune system against cells that bind to the icon. A replication-incompetent adenoviral vector was used to deliver the gene encoding the icon to the tumor cells. The tumor, once infected, produces and secretes the icon into the blood, where it circulates throughout the body seeking tumor blood cells.

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

Garen and Hu first generated human prostatic and melanoma tumors in mice, then injected the vector into one of the tumors. A control group of mice received a blank vector; those mice died within 63 days after tumors appeared on the skin.

In the mice that received the icon molecule, tumor cells were eliminated and the mice remained free of the disease for at least 194 days. They received their last injection of the vector on the experiment’s 53rd day, suggesting that the molecule’s effects are long-lasting. In addition, the icon acted against tumors that had not been injected with the vector, offering the possibility of a treatment for metastatic cancer patients. “This icon should work against all types of tumors that contain blood vessels,” Garen said.