Cure in a capsule
By WES ALLISON, Times Staff Writer
The methods have changed only incrementally over the years, and so have the results. Americans diagnosed with common advanced-stage cancers aren't living much longer today than they did in the 1980s.
Now cancer researchers are studying a new kind of treatment they think could help many more patients beat their disease, or at least live longer with it.
It's called molecular targeting, or targeted therapy. The idea is to identify the genetic and molecular workings of a type of cancer, then design drugs that disrupt them at key points.
The most promising drug in this new class, Gleevec, hit the market last summer. It has shown remarkable success in saving the lives of people with a common type of leukemia.
Now in the pipeline are treatments for other common cancers, including colorectal cancer, lung cancer and breast cancer. None appears to work as well as Gleevec, but studies suggest several will improve greatly on traditional treatments.
One, called Iressa, appears to stop progression of advanced lung cancer in about half the patients who try it. Another, Erbitux, has shown success in treating colon cancer and shrinking advanced-stage lung tumors.
Experts caution that no one should expect a miracle cure, and a wide range of effective treatments are five to 10 years away.
But the excitement in the oncology community is palpable as scientists at drug companies and cancer centers, including H. Lee Moffitt in Tampa, race to test compounds designed to short-circuit cancer cells.
"Everybody's waiting. No one's doing any chemotherapy trials -- there's nothing new that's going to be discovered that's going to make a difference," said Dr. Herman Kattlove, a Los Angeles oncologist who works with the American Cancer Society. "These are the new drugs."
'The whole world looks different . . .'
The sailboat once tied to his dock on Treasure Island is gone, a pastime Dane Tessler surrendered to diminished stamina and his new sensitivity to the sun. The guitar he played in the local beach bars is quiet, laid down when the pain in his finger bones became too great. He has gained a little weight.
But Tessler is not complaining. Were it not for Gleevec, he and his oncologist say, there is little chance he would be lounging at his home on Boca Ciega Bay this sunny morning, having just seen his two children off to school.
"When you almost die and you come back, the whole world looks different to you, and it looks much better than it was," said Tessler, a 45-year-old photographer who shares his new view of the world on his Web site, www.danesweb.com. "It's a good place, a much more colorful place."
Tessler likes to say Gleevec got him from a wheelchair to a bicycle in just 30 days. He was diagnosed in June 2000 with chronic myeloid leukemia, or CML, a cancer of the blood that affects 5,000 Americans each year. Most survive about five years.
For six months he tried chemotherapy and interferon, which marshals the body's own immune system to fight cancer. But the drugs ravaged his body's healthy cells while making no headway against the cancerous ones.
At the time, Gleevec had not been approved. Tessler learned through the Internet that it was working miracles for CML patients in clinical trials, but his past treatments made him ineligible for trials at the Moffitt Center in Tampa. By November 2000, with his weight and strength waning, his only chance was a bone marrow transplant.
"My doctor basically told me, "You're out of time. You have to try the transplant. You can't wait for this drug to be approved. You're not going to live that long,' " Tessler recalled.
A transplant is the only cure for CML. But one-third of patients die under the best of circumstances, and Tessler was sick and weak. His chances were put at 50-50 when he flew to Houston for an evaluation at the M.D. Anderson Cancer Center.
Even as he met with transplant specialists, he continued to press for a Gleevec trial, and doctors at M.D. Anderson found one for which he was qualified. Instead of spending the next 100 days recovering from a bone marrow transplant -- if he survived -- Tessler left Houston that weekend with a bottle of inch-long pills.
By the end of the next month, he was biking around his neighborhood.
"I'm alive when I should be dead. My blood counts have been normal for over a year."
Gleevec provides a good lesson in how molecular targeting works.
Throughout the body, cells are dying and being born at the mind-boggling rate of 20-million per second. Some are aberrant cells with unhappy genetic mutations, but the body has ways of dealing with them. Usually they self-destruct, or are killed by immune cells.
Cancer occurs when these aberrant cells escape the safeguards and multiply unchecked. They form clusters, called tumors, that eventually replace useful tissue and damage essential functions.
Chronic myeloid leukemia is marked by the over-proliferation of white blood cells, which eventually ruins the blood. A mutated gene inside white blood cells causes the disease.
Over time, the skyrocketing white cells disrupt the bone marrow's ability to make healthy blood. Patients usually die from internal bleeding or infection.
Gleevec arrests the disease before it gets this far. In essence, it fakes out the process, parking itself on the errant gene where another molecule belongs. The white cell proliferation stops.
The most recent data supplied by Novartis Pharmaceutical Corp., which makes Gleevec, shows it reverses white blood cell counts in 88 percent of patients with CML, far better than traditional chemotherapy and interferon.
Dr. Ken Zuckerman, a hematologist at Moffitt, said Gleevec does not come with the debilitating side effects of standard treatment.
"The previous (treatments) were used as a sledgehammer, to just make the cells die, and they would hurt normal cells as well as the abnormal ones," he said.
Crediting the Lord and Iressa
The hunt for molecular targets began in the 1970s, when scientists learned to dissect and analyze DNA, the 46 chromosomes that make up the human genetic blueprint. But only in the past few years have they had equipment to quickly study the 30,000 genes that exist in every cell.
That has allowed researchers to begin to determine which genes have gone awry and how the ensuing chain reactions allow cancer to thrive. Now they can search for drugs to interrupt them.
Several of the most-promising agents now in clinical trials target molecules called Epidermal Growth Factor receptors, which help the cancer grow.
These receptors, which are present in several types of cancer, act like antennae on the surface of cells. When an Epidermal Growth Factor protein chemically binds to the receptor, it sends signals to the nucleus of the cell that order it to reproduce.
Genentech was the first to market this technique. Its drug Herceptin was approved in 1998 for the treatment of metastatic breast cancer in women with a specific type of growth factor receptor, called HER2.
HER2 is found in about one-quarter of breast cancer patients, and usually portends a quick death. Herceptin extended the one-year survival rate of these patients by 24 percent.
Several others under development work even better. Dr. Jennifer Tseng, an oncologist at M.D. Anderson Cancer Center's branch in Orlando, is testing Erbitux, a drug by ImClone Systems that appears to stop lung cancer's progression in many patients.
Tseng said the tumor in her first patient has shrunk by well more than half. The woman has stopped coughing and no longer needs supplemental oxygen.
A major breakthrough for lung cancer would be tremendous, considering the toll it exacts. Lung cancer will be diagnosed in 154,000 Americans this year and will kill about 160,000. The most common cause is smoking.
Lung tumors can be surgically removed if caught early, but symptoms usually don't appear until the cancer has begun to spread. At that point, it's almost impossible to beat.
The five-year survival rate for lung cancer is just 14 percent -- the same as in 1980, and just 1 point better than when President Nixon declared a national "war on cancer" and established the National Cancer Institute.
"When I was first diagnosed, they were hopeful that because it was caught so early, the surgery alone would take care of it," said Gloria Caruso, 63, of Tampa. "But they noticed it had already spread into the lymph nodes. Once it spreads to the lymph nodes, it can go anywhere.
"At that point in time, we had to accept the possibility of terminal disease."
That was in 1998, and Mrs. Caruso is still working as a Northwest Airlines reservation agent. She just returned from a trip to Lake Tahoe with her husband, Sam. Along with the Lord, she credits Iressa.
Mrs. Caruso began taking it in February 2001, the first of 206 patients enrolled in an Iressa trial at Moffitt. It has been tested mostly in patients with end-stage cancer and no other options. The manufacturer, AstraZeneca, says that in about half the patients, it appears to shrink tumors by at least 50 percent.
Mrs. Caruso, a nonsmoker who was surrounded by smokers at work, was diagnosed with non-small cell lung cancer after an X-ray revealed a tiny spot in her upper lung. Over the next two years, despite chemotherapy, she developed two tumors in her middle chest and one on either side of her neck.
Chemotherapy and radiation failed to make much of a difference. Then she discovered Iressa on the Internet.
Mrs. Caruso might have to take it for the rest of her life, and the cancer might stop responding. But she is thankful for the time it has has given her.
The main side effect is acne, which she controls with the same medication her teenage granddaughter uses.
"Within 30 days after I started taking Iressa, one pill daily, the knot that you could feel within the hollow of my neck was gone. And within 90 days, the tumors had disappeared."
Shotguns better than rifles
As tumors grow, they need blood vessels to nourish them. Several experimental drugs are beating cancer by short-circuiting a vascular growth factor, which appears to stymie the growth of these vessels.
One of these is Avastin by Genentech. Given FDA fast-track status for the treatment of metastatic breast cancer, it could hit the market as soon as next year. It also appears to work on several other tumors, including lung cancer.
Doctors hope the science that led to molecular targeting might eventually allow them to identify and fix genetic aberrations likely to cause cancer before the cancer occurs. Moffitt is developing a functional genomics lab and advanced cancer detection center with that lofty goal in mind.
"Once we understand what the (genetic) marker is, what the message (it sends) is, not only can we try to get rid of it in advanced disease, but we can get to it before the disease develops," said Dr. John D. Ruckdeschel, CEO of the Moffitt cancer center and the lead investigator of the Iressa trial there.
But be warned: Science has been fooled before. Each of the past three decades had its so-called miracle cure, beginning with engineered antibodies in the 1970s that were designed to attack specific proteins in cancer cells, much like today's targeted therapies.
It was a solid idea, but researchers then didn't have the tools to pull it off.
In the late 1980s and early '90s the buzz was Taxol, a compound extracted from the yew tree. More recently it was interleuken 2 and interferon, which rev up the body's immune system to fight cancer.
All have helped, and some have proven successful for select cancers in some people, but none lived up to the hype. Dr. Mace Rothenberg, a cancer researcher at Vanderbilt-Ingram Cancer Center in Nashville, remembers how the media heralded the yew tree: "The Tree of Life."
"We often lose sight of the fact that cancer is hundreds of different diseases all driven by many processes, and it's unlikely that one drug or one approach will be the answer to all the cancers we have," Rothenberg said.
Dr. Russell R. Hoover, a researcher at the Whitehead Institute in Boston, said the success of molecular targeting depends on finding several pathways to block, and several signals to interrupt.
Cancer is too complex to be stopped by just one avenue, he said. "It's going to require shotguns, not rifles."
Even the same types of cancer can vary molecularly. Mrs. Caruso's non-small cell lung cancer might be different from another patient's, so drugs that work for her might fail for others.
Finding the best targets and drugs to block them means comparing thousands of genes in cancer cells to their counterparts in healthy cells, then following the chain reactions to determine their effect.
Some aberrations will be important. Others will be dead ends.
Of the 30,000 genes in every cell, scientists know the name and function of just 8,000 to 10,000.
"It's a matter of just grinding it out right now," said Kattlove of the American Cancer Society. "Grunt work. Brilliant grunt work, but grunt work."
Dr. Jack Pledger, deputy director of Moffitt and the head of basic research there, offered an insight into the challenge: Several Moffitt rearchers, led by Dr. Richard Jove, recently took aim at multiple myeloma, a fatal cancer of the bone marrow that will be diagnosed in about 14,600 Americans this year.
They found what appeared to be a blockbuster discovery: A signaling agent, called STAT3,that relays orders to genes in the bone marrow cells was present in large amounts in the bone marrow of patients with myeloma. A drug developed elsewhere interrupted the signals. In the lab it appeared to kill the cancer.
They tried it in mice, and the drug worked beautifully. In people, however, the drug could not be delivered in sufficient concentration.
But the exercise showed that STAT3 might be a valuable target, and researchers have since learned it's also found in excess in breast and prostate cancers. Jove is trying to develop other drugs to stop it.
Even as Dane Tessler revels in his new chance at life, he knows his good fortune might not last. Two friends in a Gleevec support group recently died after their cancer became resistant to the drug, just as many bacteria have developed resistance to penicillin.
If that happens, a patient will have the same options available 10 years ago: chemotherapy, or perhaps a bone marrow transplant.
Zuckerman, the hematologist, said he expects resistance to increase as more people take Gleevec longer. Most have been on it less than three years, and it will take at least seven more to evaluate the drug's true success.
"There's no evidence that it cures the disease yet," Zuckerman said. "What we're sort of hoping for, our fondest wish, is that it turns CML into a chronic disease . . . like blood pressure or diabetes."
Tessler represents the promise of molecular targeting as well as the uncertainty, and he appreciates how tenuous his new lifeline is.
If the levels of aberrant white cells in his bone marrow drop enough, he plans to have stem cells harvested, then stored. That way, if the Gleevec does fail him, he can use them for a last-chance bone marrow transplant.
"I'm aware of the fact that it could happen," he said. "I'm only as good as my last biopsy, as my last blood test."
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