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 clinical trials in humans possibly starting
within 2 years.
The study, published in the January 24th issue of Science, shows
that human coagulant proteins can be targeted to the cells lining vessels
that deliver blood to tumors. Cutting off the blood to the tumor kills
the cancerous cells by depriving them of oxygen and nutrients, said Dr.
Philip Thorpe, professor of pharmacology at UT Southwestern and holder
of 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's
Hamon Center for Therapeutic Oncology Research. "Then we took a human
coagulant protein, called tissue factor (TF), and targeted it so that blood
clots 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 reached
the tumor, scientists altered the genes for TF. This engineering deleted
the part of the molecule that allows it to associate with normal cell membranes.
"That renders our protein soluble so that it can be targeted to
the cancer's blood vessels. When it arrives in the tumor vasculature, it
sticks to the endothelial cells that line the vessels. This brings the
tissue factor into contact with the cell membrane, enabling coagulation
to 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 approximately
2% to 5% of their body weight. The size of these malignancies would be
the 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 cell
death was seen throughout the tumor. At 14 days, 38% of the mice had only
fibrous scar tissue visible where the neuroblastomas had been. In other
words, the rodents experienced complete tumor regression.
"What is remarkable about this treatment is that it is so effective
on large tumors and appears to be safe," Thorpe said. "We have
observed little or no toxicity using this method."
Markers in Human Blood Vessels Sought
The researchers are now trying to find markers that occur naturally
on 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 vascular
endothelial growth factor, or VEGF. Virtually all solid tumors secrete
VEGF, which binds to its receptor on the endothelial cells. Antibodies
against VEGF have been shown to localize specifically to tumor vessels
in guinea pigs in research done by Dr. Hal Dvorak and colleagues at Harvard
University Medical School. That work has been verified in Thorpe's laboratory.
"So, we have a good coagulation method, and we have a good method
for targeting human tumor vessels," Thorpe said. "We hope to
merge those two to produce an effective treatment for cancers in people."
All major types of cancer, including breast, colon, lung, and ovarian
cancer, are expected to respond to the therapy.