The Promise of the 'A' word
Finding treatments to provoke antiangiogenesis is one of the fastest-growing areas of cancer research
By Robert Levy
No cancer therapy has made the shift from scientific heresy to cause celebre as dramatically as antiangiogenesis, the notion that tumors will shrivel as their blood supply dwindles.
The colon cancer drug Avastin™, which attacks blood vessels that feed tumors, has been watched closely by Dana-Farber researcher Joseph Paul Eder, MD.
For years, it had been the all-consuming quest of Judah Folkman, MD, of Children's Hospital Boston. In 1997, antiangiogenesis sprang into the headlines when Folkman's lab isolated a natural substance called endostatin that blocks the growth of blood vessels in mice. The next year, a front page article in The New York Times quoted a Nobel laureate, whose enthusiasm may have clouded his judgment, that a cancer "cure" was at hand. Funding for a field once dismissed as fantasy land began flowing from government and private sources, attracting a cadre of able young researchers.
Today, seven years later, where does the field stand? The general public can be excused for wondering: After the thunderbolt of the Times article, coverage of more recent antiangiogenesis research has been decidedly muted.
News accounts of the first clinical trials of endostatin, some of them conducted at Dana-Farber, indicated that the drug didn't show much benefit at relatively low doses. But many reports failed to mention some tantalizing hints of success. Four of the patients in the DFCI group, for example, experienced a stabilization of their disease that continues to this day, some three years later.
If the public senses that advances have been slow — a perception fed by a natural impatience for new therapies — that view is mistaken. In fact, it can be argued that, behind the scenes and largely off the front pages of newspapers, progress on new antiangiogenic therapies has been proceeding faster and more successfully than almost any other class of cancer treatments in history.
The most prominent sign of this effort came last year with the introduction of Avastin™, the first purely antiangiogenic cancer drug to win approval from the U.S. Food and Drug Administration. Used to treat colon cancer, Avastin is a "monoclonal antibody," a protein aimed at a substance that helps deliver blood to tumors. Close behind it in the drug-development pipeline are two more antiangiogenic agents, both in the final stages of human testing, that are expected to be approved in the next few years. An estimated 70-plus antiangiogenic drugs for cancer and other diseases are currently in development at pharmaceutical labs around the world.
"Avastin vindicates the idea that tumors can be effectively controlled by targeting the network of blood vessels that feed them," says Dana-Farber's Joseph Paul Eder, MD, who has conducted clinical trials of angiogenesis inhibitors since the early days of endostatin. "It's now universally accepted that this is a legitimate avenue for therapy. After years of being out of the spotlight, it's once again safe to say the 'A' word [antiangiogenesis]."
Eder notes that it took 10 years for Avastin to pass from its design and discovery stages through laboratory studies and trials in human patients, then on to FDA approval. That is shorter than the average 13 years of development and testing expended on most new drugs.
Tumors nourish themselves by acquiring a network of tiny blood vessels linked to the rest of the body's circulatrory system.
Despite their newfound (or newly recovered) respectability, antiangiogenesis therapies will never be a "magic bullet" against cancer — nor were they ever expected to be. They constitute a new and effective avenue for attacking the disease, but probably not a self-sufficient one. A single tumor often represents such a collection of calamities — multiple gene malfunctions, immune system deficiencies, cell-signaling errors, DNA disruptions — that most experts agree the disease can be fought successfully only with several types of agents.
Although work in antiangiogenesis began in isolation, it has become part of a new, more panoramic understanding of how cancer develops and can be fought. Where scientists have traditionally trained their attention on individual cells and, even more basically, on the genes and signaling circuits that control cells' life functions, now there's a growing interest in the interactions between cancer and the surrounding mesh of normal tissue. In this view, cancer is less a singular event — the transformation of a normal cell into a malignant one — than a continuum that involves cells in "conversation" with their neighbors.
Such a view has powerful implications for how cancer is studied and some day will be treated. By broadening their focus, researchers are coming to appreciate the many ways a cell's environment influences the cancer process, and vice versa. Because the blood vessels that feed tumors are a key part of that environment, antiangiogenesis research fits neatly into the new perspective.
At Dana-Farber, the field has attracted a wide range of scientists. They're leading and participating in clinical studies of new antiangiogenic therapies, putting them to work against otherwise intractable conditions such as pediatric brain tumors, and investigating the signals that cancer cells use to tap into the body's bloodstream.
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