New Therapy Kills Malignant Tumors by Coagulating Their Blood Supply

March 1, 1997

By engineering proteins that coagulate the blood that feeds malignant tumors, scientists at UT Southwestern Center at Dallas have succeeded in destroying malignancies in mice. This therapy is expected to be effective against all major cancers, with

By engineering proteins that coagulate the blood that feeds malignanttumors, scientists at UT Southwestern Center at Dallas have succeeded indestroying malignancies in mice. This therapy is expected to be effectiveagainst all major cancers, with clinical trials in humans possibly startingwithin 2 years.

The study, published in the January 24th issue of Science, showsthat human coagulant proteins can be targeted to the cells lining vesselsthat deliver blood to tumors. Cutting off the blood to the tumor killsthe cancerous cells by depriving them of oxygen and nutrients, said Dr.Philip Thorpe, professor of pharmacology at UT Southwestern and holderof the Serena S. Simmons Distinguished Chair in Cancer Immunopharmacology.

"We engineered the tumor to induce a marker on the vessels,"said Thorpe, senior researcher on the project conducted at UT Southwestern'sHamon Center for Therapeutic Oncology Research. "Then we took a humancoagulant protein, called tissue factor (TF), and targeted it so that bloodclots formed in the tumor vessels."

Protein Engineered to Affect Only Tumor's Blood Vessels

To ensure that the protein would not cause coagulation before it reachedthe tumor, scientists altered the genes for TF. This engineering deletedthe part of the molecule that allows it to associate with normal cell membranes.

"That renders our protein soluble so that it can be targeted tothe cancer's blood vessels. When it arrives in the tumor vasculature, itsticks to the endothelial cells that line the vessels. This brings thetissue factor into contact with the cell membrane, enabling coagulationto proceed normally, but only in the tumor vessels," Thorpe said."It's like an on/off switch."

The study involved mice with neuroblastoma tumors that were approximately2% to 5% of their body weight. The size of these malignancies would bethe equivalent of about 2 to 5 pounds in a person.

Within minutes after the mice were treated with the targeted TF molecule,the tumor's vessels were blocked by blood clots. By 24 hours, tumor celldeath was seen throughout the tumor. At 14 days, 38% of the mice had onlyfibrous scar tissue visible where the neuroblastomas had been. In otherwords, the rodents experienced complete tumor regression.

"What is remarkable about this treatment is that it is so effectiveon large tumors and appears to be safe," Thorpe said. "We haveobserved little or no toxicity using this method."

Markers in Human Blood Vessels Sought

The researchers are now trying to find markers that occur naturallyon blood vessels in human tumors so that the therapy can be tested clinically.They have two markers that they believe will work, one of which is vascularendothelial growth factor, or VEGF. Virtually all solid tumors secreteVEGF, which binds to its receptor on the endothelial cells. Antibodiesagainst VEGF have been shown to localize specifically to tumor vesselsin guinea pigs in research done by Dr. Hal Dvorak and colleagues at HarvardUniversity Medical School. That work has been verified in Thorpe's laboratory.

"So, we have a good coagulation method, and we have a good methodfor targeting human tumor vessels," Thorpe said. "We hope tomerge those two to produce an effective treatment for cancers in people."

All major types of cancer, including breast, colon, lung, and ovariancancer, are expected to respond to the therapy.