Cutting off cancer's supply lines

supply, known as angiogenesis inhibitors, have been hailed as opening a new era in cancer therapy. But a flurry of animal studies suggests that such drugs may in certain situations actually accelerate the spread of cancer. “We’re just finding the limitations of these types of agents in the clinic,” says John Ebos, a cancer researcher at the University of Toronto, Canada. “I don’t think it’s unique — various types of therapies, such as chemotherapy and radiation, also have limitations. It’s just a question of how we can overcome it.” This is a key time in the long and controversial history of these drugs. In May, the US Food and Drug Administration (FDA) is expected to decide whether to expand use of bevacizumab, the first angiogenesis inhibitor. This monoclonal antibody, sold as Avastin by South San Francisco-based Genentech, was approved in 2004 for treating metastatic colon cancer in combination with chemotherapy. It has since been approved in the United States and elsewhere for other uses, and on 31 March an FDA advisory committee recommended the drug also be approved for glioblastoma, a deadly brain cancer for which few other treatments are available. The agency’s decision is expected in May. According to regulatory papers filed in January, Genentech may before then reveal results of a clinical trial to test the use of bevacizumab as an ‘adjuvant’ used with chemotherapy in patients whose colon tumours have been surgically removed. The 2,710-patient phase III trial investigated whether those who take bevacizumab are more likely to survive without recurrence of their disease than patients who do not take the drug. “There are tens of thousands of patients with early colorectal cancer who don’t get Avastin right now,” says Geoffrey Porges, an analyst with Sanford C. Bernstein in New York City. Success as an adjuvant therapy “would open up a market at least as large as the current metastatic market”, he thinks, noting that trials testing the drug as an adjuvant for other cancers are under way. Last year, the drug racked up $4.8 billion worldwide in sales; its wholesale price is about $50,000 per year of treatment. The original idea behind bevacizumab and other angiogenesis inhibitors was championed by Judah Folkman of Harvard Medical School. In 1971, Folkman wrote in the New England Journal of Medicine that all tumours depend on the constant growth of new blood vessels, a process called angiogenesis, and that blocking it should eliminate the cancer. The popularity of the idea waned in the early 2000s following disappointing results in clinical trials of two anti-angiogenic compounds, angiostatin and endostatin, that were discovered in Folkman’s lab. It regained ground when bevacizumab was approved. Since 2004, two other angiogenesis inhibitors have been approved in major markets worldwide: sunitinib, sold as Sutent by Pfizer, for use in advanced kidney cancer and gastrointestinal stromal tumours, and sorafenib, sold as Nexavar by Bayer, for use in kidney and liver cancer. Both are small-molecule drugs that target kinases, in particular vascular endothelial growth factor, or VEGF, which is also targeted by bevacizumab. Many more such compounds are in late-stage clinical trials (see table). But these drugs have not been the magic bullet that Folkman envisaged. In major cancers, such as breast and colon, they have helped patients to survive longer when given with chemotherapy, but not when given alone. The drugs seem to grant most patients slower progression and a few extra months of survival — a real benefit, but not a cure.