Angiogenesis Therapy Moves beyond Cancer

Doctors in different subspecialties, have, over the years, learned that people with Down syndrome have unsurpassed protection against certain diseases. Cancer is almost unheard of among people with this syndrome, according to oncologists. Noncongenital heart problems rarely afflict this population, according to cardiologists. And diabetic retinopathy never develops among people with both Down syndrome and diabetes, according to endocrinologists. But, until recently, most doctors only knew that Down syndrome provided protection; they did not know why. They knew that people with Down syndrome had 3 copies of chromosome 21 (trisomy 21), but no one made the link between the extra chromosome and the protective effects of Down syndrome. Then, in 2003, researchers discovered that the extra copy of chromosome 21 in Down syndrome provides the body an extra copy of collagen XVIII, from which endostatin is derived. Endostatin plays a key role in inhibiting angiogenesis, the growth of blood vessels. Uncontrolled growth of blood vessels is a characteristic of cancer, heart disease, and diabetic retinopathyall the diseases that Down syndrome protects against, apparently because of the powerful inhibiting effects of all that extra endostatin. Isn't it amazing? The endostatin appears to protect them against these seemingly disparate diseases, said Judah Folkman, MD, director of the vascular biology program at Boston's Children's Hospital and professor of cell biology at Harvard Medical School. The endostatin findings provided proof that these diseases are not, in fact, so disparate after all, and brought focus to the fact that many diseases besides cancer arise from the same process of pathologic angiogenesis. In the past 20 years, researchers have identified more than 70 diseases that depend on angiogenesisvarious types of cancer, heart and vascular diseases, many eye disorders, rheumatoid arthritis, Crohn disease, psoriasis, and endometriosis, among others. Angiogenesis researchers have long worked to use blood vessel growth inhibitors to stop cancerwithout knowing it, they were trying to recreate the environment that Down syndrome creates naturally. After struggling for many years to translate preclinical successes into the clinic, they have started to make advances at last. Earlier this year, the U.S. Food and Drug Administration (FDA) approved the first drug specifically designed as an angiogenesis inhibitor, bevacizumab for colorectal cancer. The FDA is expected to approve at least 3 more angiogenesis-inhibiting cancer drugs soon. Now, with research on angiogenesis in cancer flourishing, researchers hope to do the same thing with the other diseases that depend on angiogenesis. For the first time, Avastin [bevacizumab] showed us that there is biological activity for angiogenesis inhibitors in the clinic for patients with cancer. It proved that there is clinical meaning to developing these agents and this field of research, and it has added urgency to expanding angiogenesis research not only for cancer, but also for other angiogenesis-based diseases, said Steven Libutti, MD, senior investigator at the National Cancer Institute, Bethesda, Maryland. As occurred with the cancer research, efforts to apply angiogenesis therapies to other diseases have faced setbacks as well. Angiogenesis researchers can cure heart disease in mice but trials in humans failed, for instance. Most trials for other diseases are still in the early stages. There remain many new frontiers of basic research ahead for the angiogenesis field, but clinicians are now practicing medicine using FDA-approved treatments such as Avastin and Regranex [becaplermin, an angiogenesis-promoting ointment that stimulates wound healing]. In the future, we will not only have more therapeutic products to prescribe, but also better methods to deliver them selectively to diseased tissue. We will also be able to tailor specific therapies to specific patients on an individual basis, said William Li, MD, president and medical director of the nonprofit Angiogenesis Foundation in Cambridge, Massachusetts. More than 60 antiangiogenesis drugs are in clinical trials, many of them for diseases other than cancer; in addition, many proangiogenesis drugs for treating heart and vascular disease are being studied. As these drugs advance through trials, physicians will learn whether the promise of angiogenesis therapy for diseases beyond cancer is real. How Angiogenesis Therapies Work The body regulates normal, physiologic angiogenesis as needed to repair damaged tissue, but blood vessel growth can turn pathologic when the normal control mechanisms are disrupted. Pathologic angiogenesis supports not only solid tumor and leukemia growth but also chronic inflammation, cartilage damage, atherosclerotic plaque formation, and scarring in the eye, among other harmful processes. Abnormal angiogenesis appears to occur when cancer or other diseases control the normal processes of angiogenesis, a process triggered by the so-called angiogenic switch. The angiogenic switch, the precise molecular mechanisms of which are poorly understood, stimulates overproduction of proteins that promote angiogenesis by binding with receptors on endothelial cells. These proteins include vascular endothelial growth factor (VEGF), basic fibroblast growth factor, interleukin-8, and platelet-derived endothelial growth factor. The switch also downregulates angiogenesis suppressor proteins, such as thrombospondin, endostatin, and angiostatin. Using this knowledge of the control of angiogenesis, drug developers have found many ways to manipulate the action of proangiogenic proteins and antiangiogenic proteins. One significant worry about angiogenesis inhibitors or promoters is that they will destabilize normal blood vessel growth elsewhere in the body. But a report in the June 2004 issue of Nature Medicine described research that showed for the first time that endothelial cells have different molecular signatures depending on which tissue they are associated with. This suggested that angiogenesis drug developers might be able to design targeted drugs that interacted with the endothelial receptors of a specific organ but not other organs. Angiogenesis Therapy for Vision Disorders Folkman, who has pioneered the field of angiogenesis research, has trained many of the researchers who now work in the field. Ophthalmologists who started in Folkman's laboratory and are now developing angiogenesis-based therapies for ocular diseases are leading some of the most promising angiogenesis work outside of cancer. Pathogenic angiogenesis causes many eye diseases, including age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity. These diseases typically occur when blood vessels overgrow and leak; this eventually causes scarring inside the eye and death of the photoreceptors of the retina, leading to blindness. Antiangiogenic therapy for the eye has advanced quickly, in part because the blood vessels themselves are the disease that cause blindness; they are not just feeding the disease as in many types of cancer. The therapies that stop blood vessels from growing directly stop the disease. Furthermore, VEGF has been shown to be a central player in pathologic ocular angiogenesis, providing an ideal target for new therapies that can be effectively delivered locally to the eye. Ophthalmic researchers are particularly focused on finding a cure for age-related macular degeneration. Angiogenesis inhibition appears to stop 1 of the 2 forms of macular degeneration, called wet or neovascular, which causes most vision loss in age-related macular degeneration. The only macular degeneration drug on the market is verteporfin, a photo-activated dye that occludes new blood vessels. It prevents vision loss in select patients with wet age-related macular degeneration, although it is not by itself considered an antiangiogenic therapy. Two more therapies for this condition are expected in the near future, both angiogenesis inhibitors. One pharmaceutical company has completed successful phase III trials with its aptamer VEGF protein antagonist (pegaptanib sodium), and the company is submitting it to the FDA for review. Another pharmaceutical company is using a similar VEGF protein antagonist approach with its drug ranibizumab, an antibody fragment against VEGF. The company is completing phase III trials with the drug. Trials with both drugs have shown that these compounds can decrease the rate of vision loss in wet age-related macular degeneration. Experts in the field anticipate approval and launch of these 2 drugs within the next few years. At least 4 other antiangiogenic agents are in earlier stages of ophthalmic clinical trials. While these 2 therapies are promising, they require readministration every 4 to 6 weeks because VEGF is constantly being produced. Michael J. Tolentino, MD, assistant professor of ophthalmology at the Scheie Eye Institute, Philadelphia, is developing mediators of RNA interference (RNAi) against VEGF. His goal is to stop VEGF before it is even produced. Antiangiogenesis therapy has provided new hope for patients with AMD [age-related macular degeneration] and diabetic retinopathy. With continued advances in research, blindness from these conditions could be eliminated, Tolentino said. Last year, Lloyd P. Aiello, MD, PhD, at the Joslin Diabetes Center, Boston, demonstrated for the first time that vision could actually be restored in a patient by inhibiting angiogenesis. Aiello systemically administered an anti-VEGF molecule (SU5416) to a patient who had tumors in the eye from von HippelLindau disease. The patient's eyesight returned within 4 weeks, and the tumor vessels stopped leaking. Angiogenesis Therapy for Other Diseases Other promising clinical trials with antiangiogenic molecules are under way for rheumatoid arthritis and psoriasis. Phase II trials are studying the effects of infliximab and ada