Originally created 05/05/02

Jamming cancer's growth signals shows promise

EDITOR'S NOTE - Three decades into the War on Cancer, the disease still takes the lives of 1 in 4 Americans and is the single biggest killer of adults in their prime. Now, new insights into how cancer begins are leading to better treatment. This is the second of an occasional series by The Associated Press.

The first clue that Gloria Caruso's medical long shot might pay off, two years into her losing encounter with cancer, was the look she saw one day on her doctors' faces. Usually they were so grim, waiting for her with news that ranged from the bad to the very, very bad.

She had stopped in to hear the results of her latest CT scan, taken to chronicle her tumor's inexorable spread. But this time the medical people were, unbelievably, smiling.

"They were jumping up and down," she remembers. "This is not the reaction you expect to see at an oncologist's office."

Not for someone with lung cancer. Especially not for someone who had already endured so much. Doctors had cut out part of Caruso's right lung. They had put her through four horrific rounds of chemotherapy. And her cancer kept spreading.

In the months before that appointment last year, the future could hardly have looked worse. At 62, an airline reservation agent who never smoked, she was out of good options. More chemo was probably pointless. So was radiation.

But rather than give up, she worked the Internet, hoping to find an experimental medicine to try. There she ran across a pill called Iressa. Though not sold yet, it was available in some desperate cases like hers.

Iressa is one of a new class of medicines called epidermal growth factor receptor inhibitors, and it is as good an example as any of how strategy is changing in the war against cancer.

Iressa is nothing like ordinary chemo, which essentially blasts all fast-growing cells, good or bad. Instead, this drug is designed from scratch to jam only the signals that fuel the rampant growth of cancer.

Its maker, AstraZeneca, hopes to have it on the market later this year, and rival versions are likely to follow. At least 10 others are in human testing.

Iressa and its competitors are just one of the many new ideas that so excite cancer doctors these days. All are built on 30 years of research into the basic biology of tumors, into understanding precisely how a cancer cell varies from a normal one. Because these drugs zero in on these differences, they are called targeted therapies.

When all goes as planned, they stifle cancer but ignore the healthy parts. This means patients should avoid the hair loss and vomiting and other routine rigors of standard cancer medicine.

Because of Caruso's advanced disease, any new treatment was unlikely to do much good. Still, with few side effects, Iressa seemed worth a try. She started on the pills in February 2001 and a month later went in for the scan.

"The tumors had disappeared," Caruso said. "They were gone." And they've stayed gone, as best doctors can tell.

"I'd call her in near complete remission," says Dr. John Rucksdeschel, director of the Moffitt Cancer Center in Tampa, Fla., where Caruso lives. "There's some stuff I can't tell whether it is scar or active tumor. But I don't care. It is as if she didn't have widespread lung cancer. She is full of life and living it to the hilt."

No one can say how long her good fortune will last. Almost certainly the cancer is still there, even if it cannot be seen.

In the world of experimental drug therapy, Caruso is one of the rare winners. In testing so far, about 10 percent to 15 percent of end-of-the-line lung cancer patients on Iressa and rival drugs have had significant responses, although most eventually relapse and die. Doctors hope the drugs will work better if given to people in earlier stages of disease. But no one really expects these drugs to be an across-the-board cancer remedy, especially when used alone.

Still, doctors grope to explain their enthusiasm for drugs that perhaps have cured no one yet. Largely, it seems, they are excited because they believe Iressa and other targeted therapies in development are just the start of an entirely new and better way of dealing with cancer.

"We are really at the beginning of a new era in treatment," predicts Dr. Boris Pasche, an oncologist at Northwestern Memorial Hospital in Chicago. "What we do now with chemotherapy will be seen as barbaric in 10 years."

The National Cancer Institute is sponsoring more than 60 studies with Iressa and a similar drug called Tarceva that is being developed by OSI Pharmaceuticals, Genentech and Roche. Its goal is to try them on less common forms of cancer as well as search for tests to help predict who will respond best to them.

"Will they make a dramatic difference in outcome?" asks Dr. Janet Dancey, senior clinical investigator at the institute. "Well, hopefully. What's more likely is there will be a spectrum of effects. They will be highly effective in some people, mostly those with early stage disease. They will have some effect on others, and unfortunately there will be a group in which they simply won't work, because that's the nature of cancer."

The nature of cancer, of course, is its frustrating ability, seen over and over, to elude the best-planned treatments. While most tumor cells may be killed, a few often have built-in backup systems that allow them to survive. Just one of these cells in time can grow to take over the body and kill it.

Because of cancer's resiliency, most doubt any single new drug will be broadly effective. Combinations that strike at cancer at multiple points in its life cycle will probably be necessary to predictably cure it, and these are probably still years away.

But even Iressa's modest benefits are remarkable for one reason, says Dr. Roman Perez-Soler, oncology chief at Montefiore Medical Center in New York City. "The key point is accomplishing this without causing side effects, without poisoning patients. That is the breakthrough."

The main ill effect of Iressa, taken as a once-a-day pill, is a rash that looks like teen-age acne, and usually this is not much of a problem.

Iressa works - when it works - by blocking one of the main signals cancer uses to propel its out-of-control growth, stimulation of the chemical docking posts called the epidermal growth factor receptors. Cancer cells may carry four closely related versions of this signal receiver, and they can be turned on by at least a dozen different body chemicals.

Iressa gets inside cancer cells and blocks the signal that is fired off when one of these receptors, called HER-1, is stimulated. That signal is one of the driving forces that makes cancer do things it should not, including growing quickly, spreading through the body and becoming resistant to chemotherapy drugs.

"In a real way, we are attacking the control panels that provide the cancer cell with its unique properties to grow and metastasize," says Dr. Louis Weiner, chairman of medical oncology at the Fox Chase Cancer Center in Philadelphia.

The first drug to do this was Herceptin, which blocks HER-2, another of the epidermal growth factor receptors. It is useful in about a third of breast cancer patients. Last year the drug Gleevec, which blocks a different set of signals, became available for two rare forms of cancer.

Doctors are trying HER-1 and HER-2 blockers together, but they believe it may be necessary to jam three to five of these signaling pathways to completely stop a cancer. Many combinations may be necessary to cover all the possible signals at play in different cancers.

Even without these dream combinations, doctors hope Iressa and other HER-1 blockers will be useful for some of the most common cancers, including breast, prostate and colon.

At the top of the list, though, is lung cancer. This is the leading cancer killer, responsible for 155,000 deaths annually, and a truly awful diagnosis. Fewer than 15 percent of patients with it live for five years. Twenty years of clinical trials have increased the average survival by just two months.

Doctors say symptoms often ease after just a couple of weeks on the growth-factor blockers. And many physicians see an occasional dramatic response. Dr. Linda Garland of the Arizona Cancer Center remembers her first - a young woman dying of lung cancer after failing three courses of chemo and radiation. The disease had spread to her abdominal organs by the time she started on Iressa.

"The next time I saw her in the clinic, it was like seeing a different person," Garland said. "She looked and felt well. The CT scan showed dramatic shrinkage of the cancer."

That woman died in March, but on Iressa she gained seven unexpected good months, time to look after her child, take a vacation with her husband and enjoy life.

When human testing of these drugs began, many doctors were skeptical. At best, they hoped the medicines would stop cancer's spread. Shrinking tumors seemed a lot to ask.

"The drugs have pleasantly surprised us," says Dr. Vincent Miller, a lung cancer specialist at Memorial Sloan Kettering Cancer Center in New York City. "We approach things well-founded in science with trepidation and skepticism, having been down the road before with promising treatments."

The next step will be to prove the drugs actually improve survival. Four large studies are testing Iressa and Tarceva on patients with the most common form of lung cancer, known as non-small cell. The first results could be available in the fall.

For a lucky few like Caruso, though, these drugs already seem to have paid off. "I work full time," she says. "I travel. I enjoy life to the fullest. I can't say enough about this medicine. If it stops working, I'll be back on my computer looking for the next newest thing."



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