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Children's cancers

A photograph of Mark Kieran, M.D., Ph.D., and patient Adam Saraiva, 15,

Mark Kieran, M.D., Ph.D., gives patient Adam Saraiva, 15, a neurological exam. Adam was diagnosed in June 1999 with pineoblastoma, a cancerous tumor in the brain. He completed his treatment at Dana-Farber last summer and is doing well.

Another Dana-Farber investigator who is actively involved in clinical and laboratory research relating to angiogenesis is pediatric oncologist Mark Kieran, M.D., Ph.D., who also cares for children with brain tumors in Dana-Farber's Jimmy Fund Clinic.

Kieran is the principal investigator of a number of early-phase, national clinical trials of pediatric cancer patients involving several angiogenesis inhibitors: TNP-470, thalidomide (in combination with radiation), and SU-5416. Yet another early trial on which he is working is evaluating the angiogenesis inhibitor squalamine in combination with chemotherapy for children with all types of cancer. Currently, these are the only anti-angiogenic drugs in clinical trials involving children in the United States.

Kieran notes that angiogenesis inhibitors interfere with the formation of new blood vessels in different ways, from blocking the enzymes that enable the newly emerging capillaries to multiply and form new vessels to altering the shape of endothelial cells so they cannot form fully functioning tubes.

"Many people around the world are focused intensely on fully understanding this process. We're making progress, but we still have a long way to go."

— Stephen Sallan, M.D., chief of staff, DFCI

Regardless of their mechanism of action, Kieran says anti-angiogenic drugs must be administered virtually continuously to achieve the desired effect. This differs from chemotherapy, which is typically given at high doses for a period of time, followed by a rest period to allow normal cells to recover. "Anti-angiogenic therapy must target endothelial cells all the time so they don't have an opportunity to regenerate," he explains.

No evidence of toxicity

The angiogenesis inhibitor being most closely watched is endostatin, currently in Phase I clinical trials at three sites in the United States, including Boston. According to Donald Kufe, M.D., Dana-Farber's chief of Pharmacology and principal investigator of the multi-center, Boston-based trial, the early results indicate this drug is "safe and well-tolerated at high doses without any evidence of toxicity," which is encouraging news. Kufe stresses, however, that Phase I studies are designed to measure a drug's safety, and that further research is needed to determine if this drug will be effective.

Joseph Paul Eder, M.D., of Dana-Farber's Department of Adult Oncology, who oversees Boston's endostatin trial, says the next step is to give patients the drug by continuous infusion, rather than by a single infusion every day. "This approach is not only easier on patients, but also maintains constant levels of the drug, which we know makes it more potent," says Eder. Phase II trials, which are designed to evaluate the effectiveness of a new therapy in patients with a specific type of cancer, are expected to begin in mid-2001.

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.