Colon cancer drug seen as long-awaited victory

The first drug to emerge from a Harvard surgeon's 34-year crusade for a new class of cancer treatments is expected to win approval within weeks from the Food and Drug Administration, validating a field of research that now embraces more than 35 diseases ranging from Alzheimer's to psoriasis, researchers said.

The milestone of Avastin's approval for colon cancer treatment, researchers said, could be swiftly followed by other drugs for cancer and severe eye diseases based on the principle -- blocking the growth of new blood vessels -- that Dr. Judah Folkman first proposed in 1970.

After a roller-coaster ride of promises and failures, at least 12 similar drugs are in the final stages of testing, and scores more are in development at major pharmaceutical and biotechnology companies. Folkman himself is pursuing use of the drugs, called angiogenesis inhibitors, to prevent cancer.

"It has certainly changed the thinking in the field," said Folkman of Avastin's success at extending the life of colon cancer patients. "It's sort of like Sputnik."

Just two years ago, many researchers were pessimistic that Folkman's theory would yield significant benefits for patients. Six angiogenesis inhibitors in a row failed to prolong the lives of cancer patients in final tests needed for FDA approval. But the scientific believers, including Folkman, plowed on, and Avastin, which showed disappointing results in breast cancer tests in 2002, proved its usefulness in colon cancer in tests unveiled last June. When used with chemotherapy, the drug, developed by Genentech of San Francisco, extended the life of the sickest colon cancer patients -- who typically live little more than a year -- by an additional five months on average, and it had few side effects.

Doctors started counseling one such patient, Jay Roberson, about hospice benefits in late 1999 after cancer that had been cut out of his colon returned in his liver. Surgery was futile, they said, but he might consider the experimental treatment of Avastin and chemotherapy. Now 71, the Chesterfield, Missouri resident credits Avastin for an extra four years of life, allowing him to greet the birth of his fourth grandchild and to take the trips he and his wife had long planned for their retirement.

"The cancer is about the size of an orange," Roberson said. "It's stable right there. The drug keeps the tumor from growing."

Avastin wasn't a cure, as some had originally hoped, but it was a potent new tool. The drug blocks the production of a protein, called a growth factor, that fosters new blood vessels, thus starving the tumor.

"It clearly has renewed interest from the pharmaceutical companies and biotech," said Dr. William D. Figg, an angiogenesis specialist at the National Cancer Institute.

Novartis, which recently moved its research headquarters to Cambridge, Bayer, and Pfizer are among the big companies with angiogenesis inhibitors in final testing for colon, kidney, and gastrointestinal cancers, among others. Genentech is also testing Avastin for at least 10 other cancers. Scientists have identified more than 20 growth factors that spur development of new blood vessels and that are potential targets for treatment, according to the Angiogenesis Foundation of Cambridge.

Some scientists are still cautious about how useful this class of drugs will be.

While enthusiastic about Avastin, David Cheresh, a professor of immunology at the Scripps Research Institute in California, said there are still unanswered questions about how the drugs work and why they work in certain situations but not others.

"The jury is still out about how good it's going to get," said Cheresh.

Three drugs are competing to be the first of their class to treat the most severe type of age-related macular degeneration, called the "wet" form. An eye disease characterized by abnormal growth of blood vessels, it afflicts more than 1 million Americans and can cause blindness. The existing treatment slows its progression only in a subset of patients.

Officials at Eyetech, a pharmaceutical company based in Woburn and New York, said they expect to apply late this year for FDA approval of the drug, Macugen. In a yearlong study of nearly 1,200 people, the drug prevented significant loss of vision in 70 percent of patients, compared with 55 percent who got either a placebo or standard treatment, the company reported last fall. The drug, which is injected into the eye and which targets the same growth factor as Avastin, improved vision in 6 percent of patients, compared with 2 percent of those who got either a placebo or standard treatment.

Macugen grew out of work begun in Folkman's laboratory at Children's Hospital Boston by Dr. Anthony P. Adamis, now chief scientific officer for Eyetech.

Competitor drugs from Genentech and Alcon Laboratories are in final testing after showing they, too, could halt progression of the disease. Alcon has also begun testing its drug, Retaane, to prevent a less severe form of macular degeneration, which affects as many as 6 million Americans, from progressing to the more severe type. Some of the drugs also are being tested in diabetics with retinopathy, which can cause blindness.

"The angiogenesis field had a lot of naysayers right from the beginning," said Dr. Joan Miller, chief of ophthalmology at the Massachusetts Eye and Ear Infirmary, who has worked with all three companies on their eye drugs. "The success of Avastin is exciting. It gives a boost to antiangiogenesis in all the fields in which it might apply."

But she cautions that the eye drugs, like the cancer drugs, have not yet lived up to the early hopes -- in this case that they would reverse the damage and significantly improve vision with just a few treatments.

Other applications of angiogenesis inhibitors under study include a topical cream for psoriasis, an immune disorder that results in scaly red patches on the skin partly as a result of new blood vessels, according to Dr. William Li, president of the Angiogenesis Foundation. He said others are testing angiogenesis inhibitors for endometriosis, the abnormal growth of the uterine lining throughout the pelvic area, and for rheumatoid arthritis, which is characterized by abnormal blood vessels in the joints and high levels of the growth factor targeted by Avastin. Li himself is exploring whether angiogenesis plays a role in Alzheimer's disease.

"No doubt, Avastin is just the beginning of an entire new era of antiangiogenesis," said Li.

Meanwhile, Folkman and his colleagues at Children's Hospital are investigating whether angiogenesis inhibitors, given to healthy people at risk of cancer, could prevent the disease.

The work, still very preliminary, is based on autopsies of trauma victims showing that most people carry miniscule tumors and on Folkman's hypothesis that "we are protected by an orchestra of natural angiogenesis inhibitors that work together to keep tumors from growing." He says there is evidence of this effect in people with Down syndrome, who rarely get solid tumors and who have high levels of endostatin, a natural angiogenesis inhibitor identified in Folkman's lab.

Folkman is investigating if it is possible to keep levels of the inhibitors high enough to prevent the small tumors from ever growing into cancer. In mice, he said, studies show that drugs such as the painkiller Celebrex and the antibiotic doxycycline raise the level of natural angiogenesis inhibitors.

"The drugs we're going to use are already in us," he said. "We're simply going to raise them a bit."

"Our major thrust," he added, is: "Could we ever get to a point where we could treat cancer before even seeing it?"

Alice Dembner can be reached at Dembner@globe.com.