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Normal cells unharmed

One potential advantage of this approach is that angiogenesis inhibitors target only the cells, called endothelial cells, that comprise the newly formed blood vessels. This leaves cells in normal vessels, as well as other cells in the body, unharmed. Standard chemotherapy targets rapidly dividing cells, including many normal cells, which limits the doses that can be safely administered and causes side effects such as hair loss, nausea, and fatigue. Moreover, tumor cells mutate quickly, ultimately becoming resistant to chemotherapy, whereas endothelial cells do not.

Endostatin, a potent angiogenesis inhibitor discovered by Michael O'Reilly, M.D., of Folkman's lab, which causes tumors in mice to regress to a microscopic, dormant state, is the best known anti-angiogenic agent, but it is only one of dozens that have been identified. Many anti-angiogenic drugs are now in clinical trials involving patients with a wide variety of cancers. Some of these are showing considerable promise either alone or in combination with other drugs or forms of treatment. A number of these investigations, including the early trials of endostatin, are being conducted by researchers at Dana-Farber.

An illustration of blood vessels

A realistic hope

One Dana-Farber scientist evaluating the role of angiogenesis inhibitors in cancer is Kenneth Anderson, M.D. As director of the Jerome Lipper Multiple Myeloma Center, Anderson is focusing his clinical research on patients with multiple myeloma, a cancer of the bone marrow that crowds out the marrow's normal blood-forming cells. With conventional therapy — standard chemotherapy or highdose chemotherapy and stem-cell transplantation — patients' survival can be extended for three to four years, but there is no cure.

Anderson and his colleagues recently observed that multiple myeloma, like many other cancers, is characterized by increased new blood vessel formation. This prompted them to study whether angiogenesis inhibitors might benefit patients with this disease.

Indeed it has. In a recent clinical trial, one-third of multiple myeloma patients who had failed all other known therapies responded to the angiogenesis inhibitor thalidomide. Anderson and his colleagues are now evaluating new, more potent derivatives of thalidomide in clinical trials. "Either alone or in combination with other treatments, this new therapy offers a realistic hope for long-term, disease-free survival and potential cure," says Anderson.

Paths of Progress, Winter/Spring 2001

Paths of Progress Archive

Persistence pays off for Judah Folkman, M.D.

But for many years, Folkman, director of the Surgical Research Laboratories at Children's Hospital Boston, was derided by others in the research community, who thought his hypothesis that tumors were dependent on the formation of new blood vessels, or angiogenesis, was preposterous. "You could literally hear them snickering at my lectures," recalls Folkman, widely known for his self-effacing manner, kindness, and generosity.

But Folkman, who more than 35 years ago postulated the theory that tumors require angiogenesis to grow and spread, persisted despite the naysayers. And with the help of some intrepid colleagues who also had faith in his ideas, he painstakingly conducted the years of research necessary to prove his theory, over time convincing even the most skeptical of his critics.

Today, angiogenesis is one of the hottest areas of scientific research, generating more than 30 published scientific papers every week and spurring some 100 companies worldwide to work on it.