Angiogenesis Inhibitors: Attacking the Supply Lines
Classic wartime military strategy includes not only attacking an enemy's troops, but also destroying its supply lines - its bridges, roads and airfields. So it's only logical that in the ongoing war against cancer, scientists would explore not only tactics that attack cancer cells directly, but also those that inhibit the processes by which tumors get their sustenance.
The fact is most solid tumors, like any other cells, can't grow beyond the size of a pinhead unless they develop an independent blood supply in order to receive oxygen and nutrients. Proteins that help bring the blood supply to the tumor are called angiogenic factors. The idea that by interrupting the angiogenesis process, tumors could be starved to death - or at least have their growth stunted - was first proposed more than 30 years ago by Harvard University's Dr. Judah Folkman. Folkman's ideas, however, were met with skepticism within the scientific community. But as more of these proteins were identified and scientists began using anti-angiogenic agents to eradicate tumors in mice, angiogenesis inhibition emerged as one of the most promising new strategies for treating cancer in the last decade. Today, some 20 different anti-angiogenic drugs are in various stages of clinical testing.
|
|
||||||||
"This provides us with an additional target - namely the cancer's blood supply - that we can attack, along with the cancer cell," says Dr. Fairooz Kabbinavar, who heads one of a handful of trials at UCLA looking at anti-angiogenic therapies. Kabbinavar has just completed Phase II testing of an antibody to one of the most potent angiogenic factors, vascular endothelial growth factor, or VEGF, which has been administered in combination with chemotherapy to patients with advanced lung or colorectal cancer.
Kabbinavar, who participated in the basic research on the VEGF antibody as a member of Slamon's UCLA laboratory, is currently completing data analysis. Based on recent evidence suggesting that angiogenesis plays an important role in the progression of prostate cancer, Kabbinavar's group has also conducted laboratory experiments using their prostate- cancer model, in which they found the anti-VEGF drug worked effectively in combination with Taxol, a chemotherapy agent, and Lupron, a drug used in hormone therapy. Based on the results, Kabbinavar anticipates opening clinical trials for advanced prostate-cancer patients in the near future.
It's always a big leap from mice to men," says Kabbinavar. "There are a lot of theoretical advantages to this strategy, and we're hoping we can translate these results from looking good on paper to being effective in clinical practice. We're encouraged by what we've seen."
VEGF is important to the angiogenesis process, but it is not the only factor. Assistant Professor of Surgery Dr. Mai Nguyen, who trained in Folkman's lab at Harvard, has embarked on a gene-discovery project designed to uncover new proteins and describe their role in tumor angiogenesis. "The field has a lot of molecules already, but there are still many more to be discovered," says Nguyen. Indeed, her group has already identified 500 candidate genes through the molecular-biology technique known as suppressive subtraction hybridization.
Nguyen is also among the first scientists to seek out whether angiogenic factors can serve as tumor markers, aiding in early cancer-detection efforts. While a member of Folkman's lab, Nguyen's research found that angiogenic factors can be significantly elevated in the serum and urine of breast-cancer patients. Following up on that research, Nguyen, along with Dr. Helena Chang, director of the Revlon/UCLA Breast Center, has launched a clinical study to determine which, if any, angiogenic proteins have the potential to serve as diagnostics for breast cancer.
"Since we know that mammograms can miss up to 20 percent of breast cancers, we hope to find a screening tool that would complement mammography," Nguyen explains.
|
|
||||||||
In a third project, Nguyen is collaborating with the UCLA Center for Human Nutrition on a basic study aimed at identifying naturally occurring anti-angiogenic agents. Among such nutrients, Nguyen and colleagues are taking a closer look at soy and green tea, which epidemiological and laboratory evidence indicates produce anti-angiogenic effects.
Meanwhile, Assistant Professor of Molecular, Cell and Developmental Biology Luisa Iruela-Arispe, a former member of Dr. Harold Dvorak's group at Harvard - the scientist who discovered VEGF - has focused on identifying the natural molecular processes by which blood vessels are inhibited, hoping eventually to apply such knowledge toward the creation of agents that would stimulate the body's natural processes to work against growth of new blood vessels in tumors. "Most of the anti-angiogenic trials now are either blocking angiogenic factors or blocking their activators," explains Iruela-Arispe. "We are looking to mimic natural inhibitors."
Last summer, Iruela-Arispe and colleagues, working with Human Genome Sciences, Inc., reported that they had discovered two human proteins that inhibit the growth of endothelial cells, which are critical to new blood-vessel formation. METH-1 and METH-2 were found to have more potent anti-angiogenic capabilities than endostatin and thrombospondin, two other human proteins known to have anti-angiogenic effects. Iruela-Arispe's team is now testing whether recombinant versions of the proteins act the same in vivo as they do in vitro. The next step will be a structural-function analysis to determine the minimal region in which the molecules can have the desired functions. Once that is complete, there is the potential for collaboration with a biotech company to develop new drugs. At the same time, Iruela-Arispe is continuing efforts to identify similar proteins.
"There is a lot of excitement in the field based on laboratory and clinical results showing anti-angiogenesis therapy to be a powerful tool in suppressing tumor growth," notes Iruela-Arispe. "It's just a matter of determining which are the most effective combination of therapies for a particulat tumor."
Like Dr. Iruela-Arispe, Dr. Lee Rosen, director of UCLA's Cancer Therapy Development Program, believes that there may not be one "best"strategy. Instead, as with chemotherapy, he sees the use of a number of tactics in various combinations. "I think we're only at the tip of the iceberg in terms of understanding the angiogenesis cascade," he says. "We know a lot, but we have much more to learn before we can say exactly how the tumor creates new blood vessels. As we learn more about which of these drugs is useful in the clinical setting, we're also learning more about the pathways."
While Kabbinavar has been testing the anti-VEGF antibody, Rosen has moved to Phase III testing of SU5416, a drug that blocks a VEGF receptor in advanced colorectal- and lung-cancer patients. UCLA is the lead site for these Phase III studies that will involve 710 patients, open throughout the U.S., Canada and Europe. Rosen also heads a Phase I trial of SU6668, a second-generation oral version of SU5416 that blocks two additional receptors. Another anti-angiogenesis drug, part of a class of matrix metalloproteinase inhibitors, is being tested in advanced lung-cancer patients at UCLA in a Phase III trial headed by Dr. Robert Figlin.
"We're all encouraged by the basic science and the promise of this strategy, but we have to emphasize that it's still very early," Rosen says. "We're not at the point where we can call these miracle drugs. They do represent a new way to attack cancer, and that's very exciting."