The Goal: Control Blood Vessel Development

Managing blood vessel development by preventing its growth from tumors in cancer patients or stimulating its development in cardiac disease patients is apparently an idea whose time has come. William Li, president and medical director of the non-profit Angiogenesis Foundation in Boston, notes that using such control as a way to fight disease interpenetrates highly varied fields of medicine. "Angiogenesis is a common denominator in many of society's most significant medical conditions," says Li. He adds that when knowledge is integrated effectively, this single approach of angiogenesis research can contribute to conquering these conditions and can actually create an entire new field of medicine based on angiogenesis. It's an idea that the pharmaceutical industry has embraced. According to a recent Business Communications Company report1; angiogenesis drugs are expected to be a $2.4 billion market by 2006. The report estimates that 300 angiogenesis inhibitors for cancer treatment strategies are being developed and that another 30, designed to simulate blood vessel growth to fight cardiovascular diseases, are in the works. Control: A New View of Treatment Aside from cancer and heart disease,2 understanding and controlling blood vessel development could be an important part of treating diabetes and other diseases that lead to blindness, chronic wounds, or psoriasis. Anti-angiogenic therapy has never focused on curing cancer, according to Li: "What it has been about is controlling cancer growth by cutting off the tumor's blood supply." Consequently, he says, a cancer patient might be on anti-angiogenic therapy for a lifetime, with the drugs stabilizing the disease in much the same way that patients take statin drugs to control cholesterol levels or blood pressure medicine. "You're talking about a potentially life-threatening disease that you take a simple medicine [for] that doesn't eliminate the disease, but controls it. We're looking at the conversion of cancer from an acute lethal illness into a chronic manageable disease," he says. Control doesn't necessarily include tumor shrinkage, according to Gerald Batist, head of the oncology department at McGill University in Montreal. "In animals, when you give them angiogenesis inhibitors, tumors shrink. We don't think that's going to happen in humans. There have been thousands of people treated with various anti-angiogenic molecules and there have been very few examples of tumors shrinking. Most often what we see are lots of patients ... where the investigator says, 'These patients with metastatic lung cancer have all lived more than a year, more than we would have expected,' so it's an impression of stabilization of the tumor, because they can no longer grow for lack of blood supply." Isagani Chico, a medical officer in the Food and Drug Administration's division of oncology, agrees that using common endpoints, like tumor shrinkage, to measure a drug's efficacy may not be applicable to angiogenesis inhibitors. He says in the past, the FDA has used other endpoints, such as survival and stabilization of tumor growth. But Gerald Soff, associate professor of medicine at Northwestern University, Evanston, Ill., maintains that angiogenesis inhibitors can shrink tumors. "Angiogenesis inhibitors may not be the home run that everyone is hoping, but I do believe they will give good clinical responses by themselves, and I do believe there will be better responses combining them with cytotoxic therapy, whether it's radiation or chemotherapy," he says. Soff points to a study conducted by his team in which the angiogenesis inhibitor angiostatin enhanced radiation's tumor-killing effect on human lung cancer tumors that had been transplanted into mice.3 The Soff group also has begun early stage clinical trials exploring the effect of natural angiostatin, formed in vivo by combining tissue plasminogen activators with free sulfhydryl donors which are found in blood-pressure control medications and other drugs. His preliminary work in cancer patients "on a compassionate use basis" has shown that angiostatin produced in this manner does shrink tumors. Inhibitors on Trial Phase III trials are underway for the drug Nevostat produced by Aeterna Laboratories in Quebec City, Quebec. Developed from the spinal cartilage of dogfish sharks, the drug blocks the receptors for VEGF (vascular endothelial growth factor), a key angiogenic molecule that helps start the blood vessel growth process. Neovastat also induces apoptosis in blood vessels by stimulating caspases to block MMPs (matrix metalloproteinases), enzymes which break down tissues and allow blood vessels to grow out from tumors permitting metastasis. The caspases also induce the body's production of angiostatin, "up to 10 times" the natural amounts, says Eric Dupont, Aeterna CEO. Neovastat, he says, activates the body's natural tissue plasminogen activator, part of the body's own angiostatin-manufacturing machinery. Another VEGF inhibitor, SU 5416, recently failed during its Phase III trial. (See "Learning from Angiogenesis Trial Failures," Page 33). Made by Sugen Pharmaceuticals in San Diego, the drug was designed for colon cancer. Lee Rosen, assistant professor of medicine at University of California, Los Angeles, who had been involved in these trials, notes that as important as blocking VEGF might be, it is not the whole story. There are other molecules involved in angiogenesis, such as fibroblast growth factors, and platelet-derived growth factor. Because these and possibly other molecules play roles in blood vessel growth, "blocking only VEGF is not going to be enough," says Rosen. It will likely take some sort of orchestrated approach incorporating a number of compounds inhibiting various angiogenesis agents to treat cancer, if indeed, the anti-angiogenesis approach proves valid. A multi-drug approach may be what is needed in using angiogenesis stimulators because of the complexity and number of molecules involved in blood vessel growth, says Michael Simons, chief of cardiology at Dartmouth Medical School, Hanover, N.H. Presently, though, single drugs are being developed and tested individually. Stimulating Blood Vessel Growth Currently in Phase II trials is GenVec's drug, BioBypass, for treatment of peripheral vascular disease (PVD). The Gaithersburg, Md. company is working with Pfizer Inc. to reduce the blockage or narrowing of the femoral artery associated with PVD that affects between 5 million and 6 million people in the US, says GenVec CEO Paul Fischer. The result is pain and sharply diminished physical activity. Diabetics are especially vulnerable to the disorder, for which there is no satisfactory treatment. BioBypass is a form of the VEGF gene. A number of pre-clinical and early stage clinical trials have shown that the drug, delivered by adenovirus, is well tolerated and effective.4 While Fischer says the notion of multiple angiogenic stimulators is "interesting," he defends the value of using VEGF alone, describing it as the "most important" of the angiogenesis factors, which can "turn on a cascade of events in the body that leads to formation of new blood vessels." Courtesy of Chris ReinhardtChris Reinhardt Another solo angiogenesis stimulator that is undergoing clinical trials is FGF4. Generx, made by Collateral Therapeutics of San Diego, is being tested on about 1,000 patients suffering from angina pectoris, chest pain caused by constricted heart arteries. As with BioBypass, it is delivered by an adenovirus. With both Generx and BioBypass, the drugs' effectiveness is measured by the patients' ability to walk pain-free on a treadmill for several minutes. Explaining the choice of FGF4, company president Chris Reinhardt states, "None of us knows which is the optimal, perfect gene. We happen to believe FGFs may be more productive because they are upstream. We believe that potentially the FGF genes turn on a variety of VEGF genes. FGFs may regulate the production of VEGFs." Harvey Black (hblack@chorus.net) is a freelance writer in Madison, Wis. References 1. "Angiogenesis inhibitors and stimulators: Therapeutic strategies," Business Communications Company, Norwalk, CT., November 2001. www.buscom.com/biotech/ 2. H. Black, "Angiogenesis—promoting and blocking—comes into focus," The Scientist, 12[9]:10, Apr. 27, 1998. 3. H.J. Mauceri et al., "Combined effects of angiostatin and ionizing radiation in antitumour therapy," Nature, 394:287-91, 1998. 4.T.K. Rosengart et al., "Six-month assessment of a Phase 1 trial of angiogenic gene therapy for the treatment of coronary heart disease using direct intramyocardial administration of an adenovirus vector expressing the VEGF 121 cDNA," Annals of Surgery, 230:466-72, 1999. Common Denominators IN FOCUS | Mignon Fogarty Courtesy of Judah FolkmanJudah Folkman Considered the father of angiogenesis, Judah Folkman first recognized its importance in tumor growth. Folkman, professor of pediatric surgery and cell biology at Children's Hospital in Boston, has studied angiogenesis since the field's inception 30 years ago, and points out that different kinds of angiogenesis inhibitors (AIs) exist, some of which are likely to be more successful than others. Folkman responded to some questions from The Scientist in a 4 1/2 page document. Select comments about the common denominators in the recent AI failures are presented below. "It is important to understand the difference between indirect and direct angiogenesis inhibitors. [The former] usually interferes with the production of a tumor cell product or its receptor," says Folkman (Using this definition, Sugen's drug SU5416 is an indirect angiogenesis inhibitor.) He explains that a problem with this AI type is that tumor cells are always mutating, and eventually develop resistance to the drug by making different pro-angiogenic factors. "In contrast, direct angiogenesis inhibitors directly block vascular endothelial cells from responding to a wide range of growth factors," he notes. "Many of these inhibitors are natural endogenous proteins, and therefore have far less side-effects and less risk of drug resistance." Direct AIs can maintain stable disease much better than chemotherapy because of this ability to combat drug resistance. Folkman also points out that measuring efficacy in early AI trials is difficult: "There are, as yet, no really good surrogate markers that predict biological activity of angiogenesis inhibitors. Thus, one must still rely on CAT scans and magnetic resonance imaging to look for tumor stabilization and tumor shrinkage." Although people have experimented with using microvessel density as an early indicator of a drug's success, Folkman says, "Microvessel density, which is very good for prognosis, is not as useful for measuring efficacy of angiogenesis inhibitors." It is important to remember that patients entering trials are extremely ill and have already failed numerous treatments, according to Folkman. Moreover, murine tumor models have proven less than ideal for human disease. Despite all these issues, Folkman says he believes that AIs are faring well. "There are 24 angiogenesis inhibitors in clinical trial in the US in more than 110 centers. Seven have reached Phase III trials out of 24, which is pretty amazing.... Hundreds [of drugs] fail in phase I, and you don't even hear about it. It is good to make it to Phase III."

The Goal: Control Blood Vessel Development

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