Treatment with a protein fused to an antibody in tumor-bearing mice led to coagulation of the blood within the tumor blood vessels, tumor tissue death, and tumor growth delay, according to a new study in the May 18 issue of the Journal of the National Cancer Institute.
The tumor vasculature has become an attractive target in the treatment of cancer. The U.S. Food and Drug Administration approved the first antiangiogenic cancer drug, bevacizumab (Avastin), last year, and other drugs in this category are under development. One approach in the design of these treatments is to develop molecules that effectively induce coagulation in the tumor vasculature when delivered systemically (i.e., intravenously) but that do not induce coagulation in nontumor vessels.
Claudia Gottstein, M.D., of the University Hospital Cologne in Germany, and colleagues created fusion proteins consisting of soluble tissue factor (sTF) genetically fused to antibody fragments directed against mouse or human vascular cell adhesion molecule 1 (VCAM-1), an antigen found on the inner surface of tumor blood vessels, which is the first site within the body that is exposed to intravenous drugs. They examined the activity of the proteins in laboratory studies and tested their antitumor effects when administered systemically to mouse models of human Hodgkin lymphoma and small-cell lung carcinoma and a mouse model of small-cell lung carcinoma that contained human tumor vasculature.
A single systemic administration of the fusion protein led to tumor tissue death. Long-term treatment produced delays in tumor growth and some tumor regressions. The researchers could find no evidence for the development of blood clots or cellular death in normal tissues related to the treatment.
The authors note that this research is one step beyond vascular occluding drugs, which have been effective in clinical studies when applied locally but that could not be administered intravenously because they were not targeted.
In an editorial, Masahi Narazaki and Giovanna Tosato, of the National Cancer Institute, review the different approaches that have been under development to deprive tumors of their blood supply. "If vascular targeting approaches such as the one described by [Gottstein and colleagues] are developed into cancer therapeutics, they have the potential to add a powerful punch in the fight against cancer. Clearly, more work needs to be done, but the outlook is promising," they write.