Angiogenesis--Promoting and Blocking--Comes Into Focus

Blocking and promoting angiogenesis--the development of blood vessels--is a rapidly advancing strategy that offers opportunities to treat a spectrum of diseases. The strategy views blood vessel growth and inhibition as the linchpin in certain diseases. Stopping the growth of blood vessels from tumors, for instance, means there is no highway for metastasis, the spread of cancer from its primary site. On the other hand, increasing blood vessel growth can help ischemic, or blood-starved, hearts. "Almost everyone you talk to has one particular goal: The cardiologists want to make new blood vessels, the allergists want to stop inflammation, the cancer specialists want to stop cancers, the dermatologists want to increase blood flow to get better skin tone and to decrease it in psoriasis," observes Robert Auerbach, a professor of biology at the University of Wisconsin, Madison. In adults, the network of blood vessels is stable. Normal angiogenesis occurs during the menstrual cycle and when the body needs to repair wounds. BURGEONING FIELD: William Huse, chief scientific officer of IXSYS Inc., describes the growth in angiogenesis research as "exponential." He says, "The field is extremely hot." Researchers at universities and drug companies large and small are in the process of developing drugs to enhance or stymie angiogenesis. According to Richard Leopold, senior director of cancer research at Parke-Davis Pharmaceutical Research Co. in Ann Arbor, Mich., at least 35 drug companies are working on angiogenesis-related drugs. Parke-Davis, a division of Warner-Lambert Co. of Morris Plains, N.J., is researching agents to inhibit as well as promote angiogenesis. "The field is extremely hot," reports William Huse, chief scientific officer of IXSYS Inc., a San Diego-based pharmaceutical firm involved in angiogenesis drug development. So intense is the work in this field that two new journals, Angiogenesis--issued by Philadelphia-based Rapid Science Publishers--and Angiogenesis Research--issued by Kluwer Academic Publishers of Dodrecht, the Netherlands--have begun publication in the past two years. Interest really has begun to grow significantly in the field, says Huse, who characterizes the growth as "exponential." And a report dated Feb. 27, 1998, from the venerable New York-based brokerage firm Lehman Brothers describes as "intense" the competition among pharmaceutical companies to develop drugs to affect angiogenesis. The report notes that four companies have Phase I trials of angiogenesis inhibitors under way; two have Phase II trials; and a dozen are doing preclinical research. Interest in angiogenesis has even resurrected a once-dreaded drug: thalidomide. Originally prescribed in the late 1950s and early 1960s to combat morning sickness, the drug caused fetal deformities. The Food and Drug Administration banned it in the United States, although it was used widely in Europe. Thalidomide is an antiangiogenic agent and, as such, is in clinical trials to study its effect on breast, prostate, and brain cancer, as well as on Kaposi's sarcoma, a disease associated with AIDS. Research focusing on the growth of blood vessels has produced surprising basic findings as well as impressive clinical results. Two of the major peptides promoting blood vessel growth are vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). A new study from a team led by Michael Klagsbrun, a professor of surgery at Harvard Medical School and Children's Hospital, Boston (S. Soker et al., Cell 92:735-45, 1998) found that VEGF may also be important in neuronal growth. Neuropilin, a receptor on nerve cells for peptides that mediate neuron guidance, is also found on blood vessel cells, according to Klagsbrun. It is identical to receptors for VEGF. "The significant question is whether there is something common between the guidance system of nerves and blood vessels," he says, and the question of whether VEGF works on nerve cells is currently being investigated. While this finding fuels new interest in--and helps researchers pose new questions about--the relationship between nerve and blood-vessel growth, the practical side of angiogenesis promotion got a big boost from a study reported in February. A team of German physicians announced a major step forward with their successful use of FGF-1, to stimulate the growth of capillaries in patients with coronary artery disease (B. Schumacher et al., Circulation, 97:645-50, 1998). FGF-1 is one of two peptides that are fibro-blast growth factors, designated FGF-1 and FGF-2. Each has a different molecular weight and structure. As a result of this first clinical trial, Schumacher and his colleagues conclude the use of FGF-1 is "a new therapeutic concept" in managing heart disease. Though they caution more clinical studies are warranted before FGF-1 can be used therapeutically, the research has won accolades. "It's a landmark study," comments Judah Folkman, a professor of pediatric surgery at Children's Hospital in Boston and a professor of anatomy and cellular biology at Harvard Medical School. Folkman, acknowledged as the founder of angiogenesis studies, discussed the therapeutic possibilities offered by understanding angiogenesis 27 years ago (J. Folkman, New England Journal of Medicine, 285:1182-6, 1971). He hypothesized that without the development of new blood vessels, "solid tumors might become completely dormant at a diameter of 2 to 3 mm. Developing a way to stop the growth of such tumors--antiangiogenesis--"may become a powerful adjunct to present methods of cancer therapy," Folkman wrote in 1971. Today, "there is proof of principle in mice for the dependence of tumors on angiogenesis, and that has now been converted to therapy [in mice]," he asserts. At the end of last year, Folkman's group reported (T. Boehm et al., Nature, 390:404-7, 1997) that a natural peptide, endostatin, inhibited and shrank three different types of tumors in mice while preventing the growth of blood vessels. Perhaps most significantly, the researchers saw no resistance to endostatin even after six cycles of therapy. (A cycle involved treating a tumor until it regressed and then allowing it to regrow.) "There's never been a demonstration before of an anti-tumor agent to which resistance didn't develop. [Resistance] has always been felt to be an inevitable process," comments Robert Kerbel, director of cancer biology research at the Sunnybrook Health Science Center at the University of Toronto. Both endostatin and angiostatin, another angiogenesis inhibitor, are fragments of proteins. Endostatin is a fragment of collagen XVIII; angiostatin is a fragment of plasminogen, a protein important in preventing blood clots from forming. Ironically, both of these angiogenic inhibitors are produced by tumors, something Folkman describes as "counterintuitive." But, he continues, angiogenesis is a balance. The production of these inhibitors wanes as cancer grows, shifting the balance to angiogenic promoters. Folkman likens the process to driving. For a car to move, not only must the accelerator be used, but also the brakes must be off. In the cancer process, the angiogenesis inhibitors are down-regulated. CANCER RESEARCH: David Cheresh, a professor of immunology and vascular biology at the Scripps Research Institute in La Jolla, Calif., is working on ways to stop angiogenesis and curb the spread of cancer. Another means of stopping angiogenesis relies on blocking integrins, molecules that coordinate signals of growth of blood vessels, explains David Cheresh, a professor of immunology and vascular biology at the Scripps Research Institute in La Jolla, Calif. Cheresh has developed antibodies that block the action of one integrin, called * v ß 3. (The v stands for vitronectin, a protein.) "What we're doing is causing cells to undergo unscheduled programmed cell death, or apoptosis," he explains. "The tumor is releasing angiogenic growth factors. We're not trying to stop that. What we're going to do is interfere with ability of the blood vessels to integrate that information. We have that antagonist in the circulation that causes the endothelial cells to die." The antibody Cheresh's lab developed is manufactured with the name Vitaxin (LM 609), under license from Scripps by IXSYS. It has just completed Phase I clinical trials, says Huse. Researchers conducting clinical trials with antiangiogenic factors face unusual obstacles, cautions James Pluda, a senior investigator in the developmental chemotherapy section of the National Cancer Institute's Investigational Drug Branch, Cancer Treatment Evaluation Program, Division of Cancer Treatment. "There are no really good, easily measurable markers for activity of many of these agents," Pluda maintains. "In many cases, drugs that work by blocking a step in angiogenesis have no good surrogate markers that the drug is having this effect." When moving into studies looking at activity, researchers should have some idea that the dose of the drug chosen is having some biological effect other than, in this case, inhibiting angiogenesis, Pluda notes. Without that surrogate, he continues, if investigators move on in clinical work but find no effect, they can be left in a quandary: Does the drug really have no effect, or was the selected dosage too low? There are other potential complications in angiogenesis. All new vessels are not necessarily alike. Auerbach is studying ocular angiogenesis, work that may lead to strategies to stop the proliferation of blood vessels, an important cause of blindness. Part of his research is an effort to determine if the proliferation of blood vessels in different parts of the eye is governed by different angiogenic factors, he explains. Blood vessels in the retina induced as a result of diabetic retinopathy may be different from those in other parts of the eye, such as the choroid or the iris. MULTIPLE PURPOSES: Different physicians have various purposes in mind for either promoting or blocking angiogenesis, says Robert Auerbach, a professor of biology at the University of Wisconsin, Madison. This is a reasonable hypothesis, Auerbach notes. "If you study the receptors on the surface of endothelial cells, you can characterize different endothelial cells as being different. Some endothelial cells have a receptor for a particular growth factor; others don't." Auerbach is establishing different cell lines from multiple parts of the eye in hopes of being able to isolate and describe these variations. As-yet-unpublished work from Folkman's lab buttresses the notion of endothelial heterogeneity in a dramatic way. Angiogenesis Research Arjan W. Griffioen, Editor-in-Chief Tumor Angiogenesis Laboratory University of Maastricht Maastricht, The Netherlands Phone: 31 78 639 2143 Fax: 31 78 639 2377 E-mail: Carolijn van den Rey at carolijnvandenrey@wkap.nl Angiogenesis Tai-Ping Fan, Editor-in-Chief Department of Pharmacology University of Cambridge Tennis Court Rd. Cambridge, U.K. CB2 1QK Phone: 44 (0) 1223 334040 Fax: 44 (0) 1223 334015 E-mail: tpf1000@cus.ac.uk http://angiogenesis.rapidscience.com IXSYS Inc. 3550 Dunhill St. San Diego, Calif. 92121 (619) 597-4990 Fax: (619) 597-4950 Parke-Davis Pharmaceutical Research Co. 2800 Plymouth Rd. Ann Arbor, Mich. 48105 (800) 521-8999 Fax: (734) 622-7158 http://www.warner-lambert.com "It has always been assumed that wound angiogenesis, tumor angiogenesis, eye angiogenesis were the same--that new vessels were new vessels; there was no difference. That's all been blown out of the water," Folkman says. In the study, endostatin, the most potent antiangiogenic agent known, had no effect on wound healing. "That was a big shock," he comments. "That means there's a discovery waiting. When you have a picture of nature and the picture's not the same [as reality], you'd better find the right picture." The difference appears to lie in two molecules, angiopoietin 1 and angiopoietin 2, which were discovered in the past two years by researchers at Regeneron Pharmaceuticals Inc. of Tarrytown, N.Y. (P.C. Maisonpierre et al., Science, 277:55-60, 1997; S. Davis et al., Cell, 87:1161-9, 1996). Angiopoietin 1 is the major regulator in capillary formation in wounds and attracts smooth muscle to coat and support the capillaries. Angiopoietin 2, which is made by tumors, counteracts angiopoietin 1, Folkman points out. "So the tumors pour out angiopoietin 2 and prevent them from being coated with smooth muscle, which turns out to make them more vulnerable to endostatin," he says. Findings like this, which reveal what Folkman terms the subtle differences in tumor-related angiogenesis and wound-related angiogenesis, may well increase as the pace of research intensifies. That angiogenesis research has opened a new window on basic biology as well as the potential for treating a wide range of diseases appears indisputable. But as research continues, it is likely that angiogenesis will be seen to be an increasingly complex process. The impact of that complexity on the development of drugs based on angiogenesis remains to be determined. * Harvey Black, a freelance science writer in Madison, Wis., can be reached online at 73773.2227@compuserve.com.

Angiogenesis--Promoting and Blocking--Comes Into Focus

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