By David N. Leff
Solid tumors, like Count Dracula, live on blood. They need a steady supply to stay alive, and grow.
So for years cancer researchers have devised strategies to strangle a tumor in its crib, by cutting off the proliferation of blood vessels that feed it. That is, inhibiting angiogenesis.
Now a new approach kills off those tumorous arterioles, venules and capillaries by damming them with blood clots. Conceptually this is like the atherosclerotic plaques that cause coronary artery infarction, and necrosis of the heart muscle.
A paper in today's Science, dated Jan. 24, 1997, introduces this blood-vessel-blocking, tumor-necrotizing ploy, in a paper titled: "Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature."
Its senior author, cancer immunopharmacologist Philip Thorpe, conceived the idea over many years, and brought it to fruition at the University of Texas Southwestern Medical Center, in Dallas.
His idea derives from the blood's domino-like cascade of clotting factors, which mobilize to stanch wounds and hemorrhages by coagulating flowing blood into solid clots. Central to the system he devised is coagulation Factor III, better known as thromboplastin or Tissue Factor (TF).
Thorpe and his co-workers truncated the TF genes so their proteins would not cause clots in normal tissue, before reaching a tumor's inner blood-vessel walls, the endothelial cells.
To test their tumor-killing technology in vivo, they injected neuroblastoma cells into the flanks of mice. They grew to 2 to 5 percent of the rodents' body weight * equivalent to a human malignancy weighing two to five pounds.
"This murine neuroblastoma cell line," explained co-author Steven King, the cell biologist who managed the in vivo experiments, "had been genetically engineered to secrete the cytokine interferon-gamma (IFN-*), which induces the Class II tumor-specific marker in this animal model." IFN-*, he added, "is one of the immuno-regulators that animals produce in response to a tumor or infection.
"The markers generated by IFN-*," King told BioWorld Today, "are not normally expressed on healthy endothelium. That way, we could get specific expression in the tumor only."
To trigger clot formation in their model neuroblastomas, the Dallas group created a double-barreled * bispecific * antibody. "One arm," King said, "recognizes the truncated TF molecule; the other, the Class II marker.
"When we mix this bispecific antibody with the TF," he went on, "the arm that recognizes TF will bind it. Then when we inject this mixture intravenously into the mouse, the Class II arm recognizes the marker molecule on the neuroblastoma. What this does is bring the clot-forming TF down into close proximity with the endothelial cell's inner surface, to which it sticks."
Within 30 minutes after treatment with this targeted tissue factor molecule, all the tumors' vessels were being blocked by blood clots. Fourteen days later, 38 percent of 21 mice experienced complete tumor regression, with nothing much left of their malignancies but scar tissue. Another 24 percent of this cohort showed partial tumor shrinkage.
"Obviously," King pointed out, this is an artificial tumor model. The number of tumors that actually secrete interferon-gamma and Class II marker molecules is relatively low.
"What we're doing now," he continued, "is investigating a lot of real-world markers that have clinical significance. One such is an endothelial-cell proliferation molecule that goes by the name of endoglin. Another is vascular endothelial growth factor (VEGF), which is secreted by virtually all solid tumors. Its job is to induce the endothelial cells to go into angiogenesis mode. It's a target of standard banti-angiogenesis therapies."
King and his colleagues are going VEGF one better. "Our favorite target," he said, "is actually VEGF in combination with its receptor. We have antibodies that specifically recognize that complex. The idea there is that the tumor environment has a lot more receptors than does normal endothelium. So we have been able to show that VEGF combined with its receptor makes a very nice target."
Thorpe expects this therapy to work in all major human cancers, notably breast, colon, lung and ovary. He foresees clinical trials within the next two years.
"So what we'll be doing for those next two years," King observed, "is really looking at different tumor vasculature markers. Right now, they are testing these on human solid tumors in immunodeficient mice.
Another concept they are exploring right now is co-administering their antibody-directed, vessel-clotting treatment with standard anticancer chemotherapy drugs.
"Actually, it's one of the things we're very excited about," King said, "with Techniclone and the prospect of its purchasing Peregrine." (See BioWorld Today, Jan. 21, 1997, p. 1.)
Anti-Angiogenesis Drug Scores In Vivo
In a separate but relevant development, Boston Life Sciences Inc. said late Thursday that its anti-angiofactor "significantly inhibited tumor growth in mice."
A cohort of animals harboring sizable human prostate tumors on their backs received the company's factor for 28 days, and "exhibited an approximate 75 percent inhibition in the growth of their tumors," the company reported. In control rodents, the malignancies doubled and redoubled in size during the same period.
"To our knowledge," stated the company's chief scientific officer, Marc Lanser, "the results of this experiment represent the first time that a recombinantly-produced, systemically administered native human anti-angiogenic protein has inhibited tumor growth, apparently by inhibiting the tumor's blood supply."
This outcome, Lanser concluded, "provides striking evidence of its potential usefulness as a treatment for metastatic cancer." *