NEWS

Angiogenesis Research Is on Fast Forward

Nancy J. Nelson

While the media and the public anxiously await the start of human trials with the angiogenesis inhibitor, endostatin, scientists are busy trying to understand the basic biology behind the delicate mechanisms that cause short bursts of blood vessel growth when needed and shut them off when the job is completed.

Several presentations at the annual meeting of the American Association for Cancer Research in Philadelphia in April confirmed that angiogenesis research is not only moving forward rapidly but becoming more complex.

"We're realizing that angiogenesis is not as simple as we once thought. We previously envisioned a single growth factor inducing an endothelial cell to make blood vessels," said Lee M. Ellis, M.D., a surgical oncologist from the University of Texas M. D. Anderson Cancer Center, Houston, who chaired a mini-symposium on angiogenesis.



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Dr. Lee M. Ellis

 
Not only is the list of factors that activate angiogenesis growing, but scientists are beginning to identify their receptors which means they can start to figure out the specific biochemical pathways affected.

"What has had a tremendous impact on the field in the last few years is the discovery of growth factors and their receptors which are largely specific to endothelial cells — VEGF (vascular endothelial growth factor) and Ang I and Ang II (angiopoietin I and II)," said Robert S. Kerbel, Ph.D., professor of experimental oncology at the University of Toronto and the chairman of an educational session on angiogenesis.

Of the nearly 20 proteins now known to activate endothelial cell growth, two, VEGF and basic fibroblast growth factor (bFGF), are expressed by many tumors and seem to be important in sustaining tumor growth and promoting its spread to other parts of the body. (Without new blood vessels to supply oxygen and nutrients, a tumor will not grow beyond the size of a pinhead.) Several compounds that block VEGF or its receptor are now in clinical trials.

Also, researchers are finding different forms of certain activators; for example, there are now at least four classes of VEGF and multiple variations of one (VEGF-A) that may have distinct functions. Activators and receptors appear to work in concert, as well.

One paper from a group at the Department of Radiation Oncology at Massachusetts General Hospital in Boston, Mass., showed that tumors implanted in mice treated with anti-VEGF therapy (an antibody to its receptor, Flk-1) initially regressed. But after 26 days, a second wave of angiogenesis occurred and the tumors continued to grow.

"The basic biology is telling us that there are multiple factors and receptors that work together," said Ellis. "Once we knock out early angiogeneisis there is a second phase which in this case is not driven by VEGF. If you withdraw VEGF, angiopoietin or other factors may be there to back it up."

Increasing Factors

Not only is the list of activators growing, but several naturally occurring inhibitors of angiogenesis have been discovered. Some, like endostatin and angiostatin — discovered by researchers in the laboratory of Judah Folkman, M.D., Harvard Medical School, Boston, — are pieces of larger molecules. One is a fragment of plasminogen that appears to be a potent angiogenesis inhibitor, the other is a fragment of collagen XVIII. Still other inhibitors include troponin I, which is present in human cartilage, and tissue factor pathway inhibitor, which plays an important role in blood coagulation.



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Dr. Judah Folkman

 
Further confounding the biology is that many other factors such as hormones and immune modulators act directly on endothelial cells. Estrogens, androgens, tamoxifen, various interleukins (Il-3, Il-4, and Il-8) and interferon-alpha are postulated to have roles in angiogenesis.

As researchers begin to piece together the interactions of all these molecules and their effects on tumors, Vikas P. Sukhatme, M.D., Ph.D., chief, renal division at Beth Israel Deaconess Medical Center in Boston, believes that certain principles are beginning to emerge.

One principle is that any given inhibitor may not work on all tumors. The evidence for this comes from experiments that showed that, when anti-angiogenesis therapy (a small peptide inhibitor of integrin, a molecule present on the surface of endothelial cells) was given to mice with brain tumors implanted both in the brain and subcutaneously, the tumors in the brain regressed, whereas those under the skin grew at the same rate as the control.

"This may mean, for example, that an inhibitor will work at the primary site of the tumor, but not at the site of each metastases," said Sukhatme. "This is because there may be a lot of heterogeneity in the capillary endothelial cells in each tumor bed."

A corollary, speculated Sukhatme, is that a particular anti-angiogenesis therapy will probably not work on all tumors from the same site — all prostate or all breast tumors, for example. This is because not all prostate tumors and the surrounding cells secrete the same activators and inhibitors — some tumors will express more bFGF than VEGF, and vice versa. The angiogenic/anti-angiogenic profile may change with tumor type, grade, or size in an individual.

(These results were confirmed in an article that appeared in Science this month. At different tumor stages, certain angiogenesis inhibitors were more effective than others.)

Several speakers speculated that angiogenesis inhibitors may work on immature blood vessels, but not on human tumors that have been growing for several years. This is because most experiments with anti-angiogenic drugs have been done with mice that have relatively fast-growing tumors, rather than tumors that have been established over a long period of time.

All of these observations led Kerbel to predict that people taking anti-angiogenesis drugs will probably develop resistance in spite of Folkman's initial findings in mice, because of the "massive redundancy in factors that affect tumor cell growth."

Michael S. Gordon, M.D., Indiana Cancer Pavillion, Indianapolis, agreed. "It is foolhardy to think that one molecule will overcome this complex micro-environment," he said.

This complexity has led several experts to advocate combinations of therapy — angiogenesis inhibitors with chemotherapy agents or radiation, or inhibitors with each other.

Folkman himself pointed out that there is some evidence in mice that combinations work better than single drugs. Data from his own lab showed that tumors in mice treated with both cyclophosphamide and TNP-470 (an angiogenesis inhibitor) totally regressed. Likewise, researchers from the laboratory of Ralph Weichselbaum, Ph.D., at the department of radiation and cellular oncology at the University of Chicago showed that a combination of angiostatin and radiation therapy elicits a better tumor response than either alone.

However, since the biological pathways of many of the growth factors and inhibitors of anti-angiogenesis are not known, it is difficult to know what combinations might be effective.

"It's very important to figure out the science behind these angiogenic molecules," said David Cheresh, Ph.D., at Scripps Research Institute in LaJolla, Calif., who is working on an anti-angiogenesis therapy that targets integrin. "Until you have a mechanism it is hard to know if combinations are going to help or hurt. You want to put drugs together that have synergistic action."

In spite of these biological limitations, many angiogenesis inhibitors have made their way into the clinic. About 20 are currently being tested in clinical trials, several are in phase III testing, and plans for drug combinations are under way (http://cancertrials.nci.nih.gov).

Endostatin, one of the molecules that received extraordinary media attention last year, is expected to move quickly into clinical trials in the fall following Food and Drug Administration approval this summer. A second molecule, angiostatin, is also moving forward. Scientists at Northwestern University in Chicago and Entremed in Rockville, Md., have shown that human angiostatin is active against mouse tumors and are in the process of making large quantities to proceed to testing in humans.

"What's exciting in my mind is the tremendous breadth of the scientific endeavor," reflected Gerald A. Soff, M.D., at the division of Hematology/Oncology at Northwestern University Medical School in Chicago.

"Angiogenesis used to be focused almost exclusively in Folkman's lab in Boston and a couple of satellites nearby. Now it's clear that a number of groups have made significant progress. Today, no credible scientist would say that inhibition of angiogenesis is not a realistic strategy to suppress cancer growth and metastases."


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