New Development in Angiogenesis Science at BI/Deaconess Lab:

Tumstatin Shows Great Promise in The Fight Against Cancer

By Susie Davidson

Advocate Correspondent

BOSTON - In a recent major development within the field of angiogenesis science, a team of researchers at Beth Israel Deaconess Medical Center have isolated a mechanism behind a tumor-fighting protein called tumstatin.

First identified two years ago in the lab of Dr. Raghu Kalluri, this naturally occurring protein found in tissue showed dramatic capability, in a mouse model, of arresting the unchecked overgrowth of blood vessels within cancerous tumors.

"In this latest discovery," says Kalluri, Associate Professor at Harvard Medical School and Director of the Program of Matrix Biology at BI/Deaconess, "we were looking at angiogenesis from another angle, the point of view of the tubes of the vessels and specifically, the structure in the tube, called vascular basement membrane. While we were

looking at how the membrane regulates angiogenesis, we found that this membrane undergoes some changes when tumors need new capillaries to grow.

"It turns out," he says, "that the proteins that are made up of this membrane contain fragments that come out when the membrane is broken down, and function as endogenous anti-angiogenic inhibitors. Tumstatin appears to act as a kind of brake, which can slow and ultimately arrest protein synthesis in cells at the edge of blood vessels, which causes new vessels to form. "The discovery of such endogenous inhibitors of angiogenesis is one of the most significant discoveries in recent times," he notes. "Seven such inhibitors have been found so far; we have studied this one a little more closely."

Is tumstatin perhaps the most effective of them all? "We do know that yet; it is very effective in mouse studies," he replies. "It has shown dramatic effects in controlling the growth of tumors. It's really difficult to make a comparison, because we know that it works in far different ways than other antiangiogenesis inhibitors. The end result

is the same, but the mechanisms vary."

Angiogenesis is a bodily process where endothelial cells, which line the inside of blood vessels, divide and separate from vessel membranes. In the process, they form tubes, which become new capillaries. This happens during a woman's menstrual cycle as uterine linings are rebuilt, and during post-injury tissue repair. But when the balance between proangiogenic and antiangiogenic elements goes awry, deleterious effects such as macular degeneration, the overgrowth of eye blood vessels, or the dividing and spreading of tumors' endothelial cells can occur.

Angiogenesis science was pioneered by Harvard Medical School's Dr. Judah Folkman 30 years ago, and has become a major player in cancer cure research. "This is a very important advance in the fields of angiogenesis research and cancer biology," states Folkman. "This discovery of the novel protein tumstatin in the body's extracellular matrix is fundamental because it enlarges our view of the family of proteins which guard against abnormal angiogenesis." While Kalluri's finding was made independent of Dr. Folkman, he states that they are colleagues. "He has been a great supporter of our work. We have different approaches, but they are within the same field of angiogenesis inhibitors. We are in constant conversation these days to find better ways to understand how these molecules work.”

Kalluri stresses the nontoxicity of the field's approach. "There are no side effects," he says, "and we hope, through these inhibitors, to potentially reduce cancer into a manageable disease." BI/Deaconess has licensed the rights to develop this molecule in a clinical setting to pharmaceutical company Ilex Oncology of San Antonio, TX. "I consult for them," says Kalluri, "but they did not fund the study in my lab." He notes that Ilex has released a press statement about upcoming clinical trials.

"The most exciting aspect of anti-angiogenesis inhibitors," says Kalluri, "is that they can be used against any type of cancer occurring anyplace within the body."