Canstantin inhibits new blood vessel growth, suppresses renal, prostate tumor growth in mice
BOSTON--Researchers at Beth Israel Deaconess Medical Center have discovered a potent new substance that thwarts tumor growth by blocking the formation and growth of new blood vessels. The naturally occurring protein is named "canstatin" for its potential cancer-halting abilities.
In a mouse model of human prostate cancer, canstatin was as effective at less than half the dose as the well-known angiogenic inhibitor endostatin in halting the growth of tumors. In mice models of renal cancer, canstatin stopped the growth or slightly shrank tumors to as much as one-fourth the size of tumors in mice treated with a placebo. The paper is published in the Jan. 14 issue of the Journal of Biological Chemistry (published online Jan. 7 at www.jbc.org ).
This is the first in a series of new angiogenic inhibitors discovered in the blood vessel wall by BIDMC researcher Raghu Kalluri and his colleagues. In addition to its preliminary promise as a cancer-fighting agent, canstatin is also relatively easy to produce in quantities that will be necessary for human clinical trials, which may begin in one or two years after further preclinical testing.
"Tumors are highly dependent on new blood vessels for their growth, and canstatin appears to stop the division of endothelial cells as they begin multiplying to form new blood vessels," says Kalluri, who is also an assistant professor of medicine at Harvard Medical School. "The agent stops them from multiplying by inducing programmed cell death only in the dividing cells, not in the non-dividing endothelial cells in established blood vessels. The tumor stops growing because it doesn't get any new blood supply or nutrients."
During the process of angiogenesis, endothelial cells that line inside of the blood vessel divide, move through the surrounding vessel walls, and form tubes that will become new capillaries. Other experiments by Kalluri and his colleagues show that canstatin can also inhibit the migration and tube formation of endothelial cells. The results suggest that the inhibitor may work at more than one step in the angiogenesis process.
"I do not believe any angiogenic inhibitor will be used as a single agent to fight cancer," Kalluri says. "They're potentially powerful drugs for controlling tumor growth, but for complete control of cancer angiogenic inhibitors probably will have to be used in combination with existing therapies, such as radiation and chemotherapy."
Other authors on the paper include postdoctoral fellow George Kamphaus, Ph.D., postdoctoral fellow Pablo Colorado, Ph.D., postdoctoral fellow David Panka, Ph.D., postdoctoral fellow Helmut Hopfer, Ph.D., postdoctoral fellow Ramani Ramchandran, Ph.D., technician Adriana Torre, postdoctoral fellow Yohei Maeshima, M.D., Ph.D., associate professor James Mier M.D., and BIDMC renal division chief and professor Vikas Sukhatme, M.D., Ph.D..
In July 1999, Beth Israel Deaconess Medical Center licensed its intellectual property rights in canstatin and four other angiogenic inhibitors derived from vascular basement membrane to ILEX Oncology, a publicly traded drug development company in San Antonio. Kalluri, Sukhatme and BIDMC all own equity in ILEX, which is developing canstatin and other compounds as cancer treatments to be used in combination with radiation and chemotherapy.
The research was funded in part by National Institutes of Health, Hershey Prostate Cancer Research award, American Society of Nephrology, National Kidney Foundation, and Beth Israel Deaconess Medical Center.
Journal
Journal of Biological Chemistry