Campus & Community

New drug Gleevec dissolves stomach tumors

7 min read

Also being tried in brain, lung, and other cancers

Ken Garabadian had 30 to 40 tumors in his abdomen. He suffered from a rare, lethal stomach cancer known as GIST (Gastrointestinal Stromal Tumor) for which no cure or treatment existed at the time.

“I thought the end was in sight,” says the 51-year-old salesman from Bellingham, Mass. Garabadian had been seeing George Demetri, at Dana-Farber Cancer Institute in Boston, and Demetri offered him a new drug that was proving effective for treating a form of leukemia totally unrelated to GIST. Garabadian, ready to try anything, began taking the new drug last July.

Dr. George Demetri and his colleagues at the Dana Farber Cancer Institute have discovered a new drug that rapidly kills tumors in a once incurable type of stomach cancer. (Jon Chase, Harvard News Office)

“In six months all my tumors were practically gone,” Garabadian exclaims. “It’s miraculous. I feel even better now than I did before the cancer, physically, mentally, and spiritually. I have no side effects and I’m working full time.”

Garabadian isn’t an isolated case. Since July, Demetri and his colleagues in Finland, Oregon, and Philadelphia have treated 148 GIST patients. Eighty-six of them have been taking the drug long enough to evaluate its results, and half of these patients showed a 50 percent or greater shrinkage of their tumors. In the other half, all but seven have enjoyed a halt to their tumor growth and have seen large bulky tumors shrink 25 to 48 percent.

“It’s totally a Lazarus experience,” says Demetri. “For many of these patients the end was near. Most of them have told me that they got their life back.”

Demetri and his colleagues described the successful use of the drug, called Gleevec, on May 14 at a meeting of the American Society of Clinical Oncology in San Francisco. Gleevec, first known as STI571, was not developed for GIST, but to treat an often-fatal type of leukemia known as chronic myelogenous leukemia or CML. In one study 53 out of 54 patients in the early stage of CML saw their cancer go into remission. Cancerous cells in seven of the patients disappeared completely. The U.S. Food and Drug Administration approved the drug on May 10 following the shortest review on record, a scant two-and-a-half months. Tests of Gleevec have been expanded to include more than 3,000 patients worldwide.

Meanwhile, researchers at Dana-Farber Cancer Institute and a few other medical centers have begun testing Gleevec on brain, lung, and prostate tumors.

Turning Gleevec on GIST

Results with GIST patients are “incredibly significant,” comments Demetri, who is also an assistant professor of medicine at Harvard Medical School. “Only 2,000 to 5,000 people in the United States have this disease, but there’s no cure for it once it spreads to the point where surgeons cannot remove the many tumors. It also serves as a model for other more common cancers. By studying GIST, we expect to learn new things about the big four killers – breast, colon, lung, and prostate cancers. Science and medicine often make the biggest leaps forward in unusual, rare diseases.”

At a conference in 1999, Brian Druker, a professor at Oregon Health Sciences University, described how he used Gleevec to treat chronic myelogenous leukemia. In this malady, white blood cells grow unmanageably, often spreading too fast to be removed by surgery or controlled by chemotherapy. The growth is caused by a mutated protein, an enzyme that stimulates white blood cells to reproduce endlessly. Druker and his colleagues found that Gleevec stops this uncontrolled activity.

Demetri compares the situation to a light switch stuck in the “on” position until the drug switches it off.

After congratulating Druker, who once trained at Dana-Farber, Demetri asked about other wayward enzymes that Gleevec might block. Druker told him that his laboratory work indicated that the drug also shut down an enzyme known as KIT. Demetri and his team recalled that, in 1988, scientists in Japan reported that GIST cells containing KIT showed uncontrolled growth. The next step, then, was to prove the KIT-GIST connection.

Demetri knew that Jonathan Fletcher, a colleague at Brigham and Women’s Hospital, across the street from Dana-Farber, was the only person in the world who kept a line of GIST cells growing in his lab. He had made these cells from a tumor taken from a GIST patient. Fletcher generously provided cells to David Tuveson and George Daniel, Demetri’s colleagues who determined that these cells contained KIT enzymes stuck in the open position. When they added Gleevec, the abnormal enzyme shut off completely in a few hours, and the cells went on to die.

An amazing response

The next thing to do was to try the same thing in a patient. The team had grown to include researchers from Finland as well as other parts of the United States. They chose a 53-year old Finnish woman who had undergone surgery and chemotherapy for GIST without success. Starting in March 2000, she began taking four yellow Gleevec pills a day. Within two weeks tumors in her abdomen and liver began to decrease.

“Such a response was unheard of with any prior type of treatment [for GIST],” Demetri notes.

On April 5, 2001, Demetri, Druker and the other team members reported in the New England Journal of Medicine that the woman had continued to improve. Side effects from the treatment were “minimal,” they wrote, consisting of mild indigestion and “a slightly increased frequency of bowel movements.”

“It was an amazing response,” Demetri exclaims. “But even if it had not been so dramatic, we were determined to push on. CML could be treated successfully by other means, but for GIST this was all we had.”

Demetri and his colleagues convinced Novartis, the Swiss drug company that makes Gleevec, to let them expand their investigation to other patients. Those experiments began last July with 148 patients, 74 of whom were treated at Dana-Farber, a teaching facility of Harvard Medical School. The patients included Garabadian and John Krupowicz, 54, a metallurgical engineer from New Jersey.

“I went through five different types of chemotherapy but I still had tumors growing in and around my liver,” Krupowicz says. “A doctor at the lab where I worked said, ‘try to stay alive two more years, something may come along by then.’ It’s uncanny how true his words turned out to be.”

Contacted by phone, Krupowicz said, “I still have tumors but they continue to decrease in size. “I’ve come out of retirement and I can do everything I did before (the disease). Last weekend, I chopped down some trees with my neighbor. I’d say unequivocally that I’d be dead now if it wasn’t for that drug.”

Krupowicz was anxious to get off the phone. He had an assignment to do for his employer, Exxon Mobil.

Demetri and his colleagues rushed their results to the National Cancer Institute in Washington, D.C., along with a request for funds to support a large study. “NCI approved our proposal, and we set a record of five weeks in getting a national study up and running, a process that normally takes two to three years,” Demetri notes.

This study began in January of this year and has enrolled more than 270 more people thus far. “We continue to experience success,” Demetri comments. “Gleevec is shrinking tumors in most of these patients, and the treatment is well tolerated,” that is it shows few side effects. “A small number of people show resistance to the drug. We think that’s because enzymes other than KIT may be involved, so we’re looking for ways to switch them off.”

Dana-Farber researchers also have begun experiments to see if Gleevec effectively attacks small cell lung cancer and brain tumors. “It’s too early to report any results from these experiments,” Demetri notes. Tests to treat prostate cancer are also planned. The drug is made by Novatis Oncology in New Jersey, which promises to make the drug available at a reduced price for those who cannot afford its cost of $2,000 to $2,400 a month.

Although results with GIST and CML have been spectacular so far, no one knows if daily doses of Gleevec will continue to keep away cancer. That thought lies heavy on the minds of both physicians and patients. “The drug saved my life,” says Krupowicz, “But for how long? We’ll just have to wait and see.”