Researcher At UCLA's Jonsson Cancer Center Discovers Two New Angiogenesis Inhibitors

The two proteins, named METH-1 and METH-2, were shown to be much more active than endostatin in preventing blood vessel formation and may have applications in creating treatments for a broad range of tumor types.

The discovery of these two proteins and their anti-angiogenic activity is described in the August 13, 1999 issue of Journal of Biological Chemistry. The paper can be accessed at http://www.jbc.org.

The team, led by UCLA molecular biologist Luisa Iruela-Arispe, found that both METH-1 and METH-2 inhibited blood vessel formation in two standard biological model systems, the cornea pocket model and the chorioallantoic membrane model.

The ability of METH-1 and METH-2 to inhibit new blood vessel formation was compared to that of both endostatin and thrombospondin, two other human proteins. The study showed that METH-1 was most potent in inhibiting new blood vessel formation, followed by METH-2, then thrombospondin and endostatin.

A solid tumor cannot grow beyond the size of a pinhead unless it has an independent blood supply to deliver the oxygen and nutrients that the malignancy needs to advance and spread. To feed itself, a tumor develops its own blood supply, a process called angiogenesis. Researchers hope anti-angiogenetic drugs can interrupt that process, thereby cutting off the blood supply to the tumor and, hopefully, killing it.

METH-1 and METH-2 act by inhibiting the growth of endothelial cells, a cell type which is key to new blood vessel formation. The studies show that neither METH-1 nor METH-2 inhibit growth of other cells required for blood vessel formation, including smooth muscle cells.

"The discovery of two novel proteins that inhibit blood vessel formation is exciting, because both proteins were shown to be more potent than endostatin or thrombospondin in preventing new blood vessel formation," said Iruela-Arispe, assistant professor in the UCLA Department of Molecular, Cell and Developmental Biology, and a member of UCLA's Jonsson Cancer Center.

"These proteins appear to be part of a larger family of related molecules, perhaps created as natural chimeras of metalloproteinase and thrombospondin protein," said Iruela-Arispe. "We believe that the original parent of such genes may have arisen 700 to 900 million years ago. Each member of the family may have a slightly different natural function."

The two proteins were found in a systematic search of the HGSI human gene database. The initial computer search was conducted to identify new genes that contain thrombospondin-like elements; the METH-1 and METH-2 genes were identified using this method.

The proteins were named "METH" because they contain elements similar to metalloproteinases as well as thrombospondins. Although similar to one another, METH-1 and METH-2 are made by different genes.

"I am very pleased with the collaboration with HGSI," said Iruela-Arispe. "We simply could not have made this discovery without the HGSI database and access to genes that they provide."

Craig A. Rosen, Ph.D., senior vice president of research and development at Human Genome Sciences, said, "By now everyone should be aware of the excitement surrounding the possible use of novel anti-angiogenic proteins as drugs to treat cancer. Endostatin and other inhibitors of blood vessel growth have been shown to inhibit the growth of tumors in animals and are currently being examined for similar anti-tumor effect in human clinical trials."

"We are encouraged that in model systems both METH-1 and METH-2 appear to be more potent than endostatin," said Rosen. "We are currently investigating the anti-tumor properties of both proteins. Providing the preclinical data remain encouraging, we plan to develop the drugs ourselves. If successful, they would add to HGS' growing list of anticancer drugs, which include Myeloid Proliferation Inhibitory Factor-1, now in Phase II trials for breast and ovarian cancers; Keratinocyte Growth Factor-2, which is about to begin Phase II human clinical trials for treatment of cancer therapy induced mucositis; and, antagonists of B lymphocyte stimulating protein, BLyS, which HGS is currently developing for potential use in treatment of B-cell lymphomas."

William A. Haseltine, Ph.D., Chairman and CEO of HGSI, said, "The discovery of METH-1 and METH-2 anti-angiogenesis proteins is testimony to the power of our technology. Working with a team of scientists at UCLA we used systematic methods to search for and find new proteins that inhibit blood vessel formation that may be useful for the treatment of cancer. We are very pleased with our collaboration with Dr. Iruela-Arispe's team at UCLA, world renowned experts in the field of anti-angiogenesis."

Co-authors from UCLA include Francisca V?zquez, Maria-Asunci?n Ortega, Timothy F. Lane, Sarah Oikemus and Michelle Lombardo. The other co-author is Gregg Hastings of Human Genome Sciences. Research conducted in Iruela-Arispe's laboratory on anti-angiogenic inhibitors is funded by the National Institutes of Health and the American Heart Association.

UCLA's Jonsson Cancer Center was among the first institutions to test angiogenesis inhibitors on patients; early phase testing was launched two years ago. Two angiogenesis inhibitors currently are in clinical trials at UCLA's Jonsson Cancer Center, one attacking colorectal cancer, the other being tested on lung cancer, with encouraging results thus far.

"The use of angiogenesis inhibitors is one of our most promising cancer-fighting strategies," said scientist Judith C. Gasson, director of UCLA's Jonsson Cancer Center. "The discovery of these two novel proteins by Dr. Iruela-Arispe is a tribute to the power of basic science research in the battle against cancer."

UCLA's Jonsson Cancer Center has more than 300 member physicians and scientists who are constantly working to develop new ways to treat, detect, prevent and control cancer. For more information on the Cancer Center, its members, research and experimental treatments, see its Web site at http://www.cancer.mednet.ucla.edu.