May 2, 2001

INTELIHEALTH FEATURE

By Lisa Ellis
InteliHealth Staff Writer

More Precise Treatment
Effective Against GI Tumor
Several Challenges To Overcome

Imagine this: a cancer drug that can be taken as a pill, one that has few side effects and attacks only cancer cells — not normal cells — by stopping the processes that make the cancer grow.

Researchers now have created several such drugs and are learning how well they work, and for which cancers.

One of the most promising drugs, cancer researchers say, is STI571 (Glivec), which is in late stages of the clinical trials required before approval for wide use. Studies published April 5, 2001, in the New England Journal of Medicine found that Glivec greatly reduced the level of disease in patients with an early stage of chronic myeloid leukemia and in a rare cancer called gastrointestinal stromal tumor (GIST).

Drugs in this relatively new class are called signal transduction inhibitors (STI's) because they interfere with the chemical signals that direct cancer cells to grow. Several are being tested in cancer patients, and numerous others in animal or cell studies in laboratories.

"Right now it's the hottest thing in cancer," said Thomas Lynch, M.D., an assistant professor of medicine at Harvard Medical School who is involved in clinical trials of an STI drug called ZD1839 (Iressa). "Every drug company involved in cancer is working on this."

"It's just remarkable how exciting it is right now, to envision a future where people can treat cancer with just pills that don't have terrible side effects," said George Demetri, M.D., an assistant professor of medicine at Harvard who was a senior investigator in the study on Glivec and gastrointestinal stromal tumor, a cancer of the connective tissues in the abdomen.

The development of signal transduction inhibitors rests on many years of research in cell biology and genetics that have helped to identify the triggers that make some cancers develop and grow. Signal transduction inhibitors turn off these triggers so the cells will not reproduce.

"What the clinical trials with Glivec teach us is that if we understand the targets in a cancer that are absolutely crucial to the growth of that cancer, then we can shut them down right at the source," said Brian J. Druker, M.D., a professor of medicine at Oregon Health Sciences University who was co-developer of Glivec and lead investigator on the use of f Glivec against chronic myeloid leukemia. Leukemia is a cancer involving overproduction of white cells. Twenty to 30 percent of adult leukemias are CML.

Novartis Pharmaceuticals AG, which makes Glivec, has applied to the U.S. Food and Drug Administration for approval of Glivec to treat CML and received priority review status, which means the drug, if approved, could be on the market by sometime in fall 2001, said Gloria Stone, a spokeswoman for Novartis.

Glivec produced outstanding results for early-stage CML and for GIST in part because researchers were able to find and shut down the initial, absolutely critical abnormality that caused the cancer cells to grow, Dr. Druker said. Glivec's success also may be related in part to the relative simplicity of CML and GIST, researchers said. The growth of each of these cancers appears to rely heavily on the activation of one particular enzyme.

The "big four" cancers — lung, breast, prostate and colon — and most others are much more complex, with multiple triggers involved in the same cancer, Dr. Demetri said. This means that in many cases the greatest benefit of signal transduction inhibitors may be in combination with other drugs (even other signal transduction inhibitors), similar to the treatment of HIV, where "you never saw much happening until you put three [drugs] together," he said.

More Precise Treatment

A major advantage of Glivec and other similar agents is that they are less likely to cause side effects because they are targeted to specific abnormalities in the cancer cells, said Anthony Murgo, M.D., an oncologist and senior investigator in the branch of the National Cancer Institute that coordinates research on new cancer drugs. "Generally in cancer therapy, the agents have effects not only on the cancer cells but also on normal cells and tissues," he said.

For instance, Dr. Druker said, the most common treatment for CML, interferon, produces flu-like symptoms so physically disabling that 20 percent of patients quit treatment. "They feel like they've got a bad case of flu every single day," he said.

Among CML patients involved in tests of Glivec, on the other hand, the side effects were mostly mild, according to an article by Dr. Druker and other researchers published in the New England Journal of Medicine. The side effects included nausea, swelling, vomiting and diarrhea.

Another advantage is that Glivec is given by pills rather than an injection such as interferon, "and it works as well as or better than interferon in the short run," Dr. Druker said. Longer-term studies are under way.

Both Glivec and Iressa work by stopping the activity of one or more enzymes in a family of enzymes known as tyrosine kinases.

Everyone has the enzyme involved in chronic myeloid leukemia, but it is rarely activated, Dr. Druker said. In nearly all patients with CML, however, two chromosomes have swapped some genetic material. As a result of this swap, he said, the gene responsible for the tyrosine kinase that regulates white blood cell production is united with another gene on the new chromosome, forming a "fusion gene."

Because the tyrosine kinase produced by this gene is faulty, Dr. Druker said, it constantly signals the bone marrow to make white cells, even when there are too many. "I look on it as a broken thermostat. It gets stuck in the 'on' position," he said.

Glivec, in effect, shuts off the thermostat, he said.

In the study published in the New England Journal of Medicine, researchers at Oregon Health Sciences University and several other medical centers reported they administered Glivec to a total of 83 patients with CML in its early, "chronic" phase who had failed to respond to interferon.

Of the 54 patients treated with daily doses of 300 milligrams or more, nearly all (53) were restored to a normal blood count, and 29 also had a reduction in the level of white cells with the abnormal chromosomes. In seven patients, the cancer-causing abnormality had disappeared from samples of white cells the researchers examined.

A separate study of patients with more advanced CML, a stage called blast crisis in which the immune system essentially shuts down, also produced improvements. Of the 38 patients with one subtype of blast crisis, 21 (55 percent) had improved blood counts and in four patients the count returned to normal. Of 20 patients with another subtype of blast crisis, 14 (70 percent) had improved blood counts and four had complete remissions. Only seven of the first group and one of the second group remained in remission, however.

Dr. Druker said he believed the more advanced disease responded less well because it is much more complicated than early-stage CML. "As the disease progresses, you accumulate many more abnormalities that the cancer uses for its growth and survival, so no one abnormality is critical anymore," he said.

But he added that the results are still significant because nothing else works well for patients in this phase of CML.

Effective Against GI Tumor

Glivec also seems to be effective against GIST, a rare gastrointestinal tumor for which the trigger of cell growth apparently is a tyrosine kinase enzyme called kit that is similar to the enzyme involved in CML.

Dr. Demetri, co-director of the Sarcoma Center at Dana-Farber Cancer Institute, said that as a result of a mutation, the kit enzyme, like the enzyme involved in CML, stays on all the time, causing untrammeled growth of the cancer. Dr. Demetri said he learned from Dr. Druker, a former Harvard colleague, that Glivec also could shut off the kit enzyme.

GIST is "notoriously unresponsive to cancer chemotherapy, and there is no effective therapy for advanced, metastatic disease," according to the New England Journal article on GIST by Dr. Demetri and colleagues in the United States and Finland.

Researchers gave Glivec to a woman who had many GIST tumors that were growing and multiplying despite several other kinds of treatment. In eight months of treatment, according to the article, the tumors shrank to a fraction of their former size, and several disappeared.

Dr. Demetri said results from a subsequent study of many more GIST patients were scheduled to be presented at the American Society of Clinical Oncology (ASCO) annual conference in May (2001), and multiple international studies were under way. "I think the fact that we've moved forward so fast with so many studies speaks for itself" about the results, he said.

Several Challenges To Overcome

Although researchers agree that signal transduction inhibitors hold great potential as cancer treatments, several challenges must be overcome. The first challenge is finding the right targets for drugs even though most cancers are so complicated that simply shutting down one cell-growth mechanism will not be enough.

Take Herceptin, an STI made by Genentech Inc. that is administered intravenously rather than taken as a pill. Already on the market for the treatment of metastatic breast cancer, Herceptin acts on a growth factor receptor on the surface of a cell rather than on an enzyme inside the cell.

But that receptor is found in, at most, only 30 percent of breast cancers, said Joan Brugge, Ph.D., a professor of cell biology at Harvard. That means "only 30 percent [of breast cancers] are even susceptible to this drug," she said.

Another problem for signal transduction inhibitors is that the targets keep moving. "The most significant challenge in completely eliminating the tumors is the genetic instability of the tumor and their ability to mutate," Brugge said. By mutating, "they find ways to get around the drug."

For many of these reasons, researchers believe much of the use of signal transduction inhibitors will be in combination with each other drugs that actually kill cancer cells instead of just stopping their growth.

Iressa, made by AstraZeneca, is being used this way in clinical trials for a variety of solid tumors, including certain varieties of lung, vulvar and prostate cancer. According to company materials that have not been published in a peer-reviewed medical journal, Iressa is believed to have caused 15 out of 64 lung-cancer patients to stabilize or improve for four months or longer, with the best results in a group called non-small cell lung cancer.

Iressa, given in pill form, acts by shutting down a tyrosine kinase inside a cancer cell that instructs it to divide.

"It's not going to replace current treatment," said Dr. Lynch, who is involved in advanced-level clinical trials that have enrolled 2,000 patients at several medical centers. "It's not going to be a home run in and of itself but it will find an important niche along with current treatments."

It is also unclear how long Iressa will help patients because long-term trials are still under way, Dr. Lynch said. Still, with lung cancer, any advance is important because the disease is so difficult to treat, he said.

The potential of STI's is "immense," he said. "It's the most exciting, significant breakthrough in cancer in 30 years. These are drugs with a very novel mechanism of action and they're showing [results] in areas where we've never seen [results] before."

Used with permission of the copyright owner. All rights reserved. This article is not intended to provide advice on personal medical matters or to substitute for consultation with a physician.