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CANCER: TURNING THE CORNER
Second of five parts
HOUSTON - INSIDE JIM Hassmann's bones, out-of-control white blood cells had taken over. Dividing unchecked, they were squeezing out the marrow that produces life-sustaining red blood cells.
Conventional drugs failed to slow his rampaging chronic lymphocytic leukemia, or CLL. ''The hematologist said there was nothing else to help me, that I was at end-stage,'' recalls Hassmann, 54, who was breathless, tired, and sick. ''And I was making end-stage plans.''
As a last resort, the Houston man was referred earlier this year to the vast M.D. Anderson Cancer Center here, where besides standard treatment, patients can volunteer for a wide range of experimental therapies, from cancer vaccines to gene therapy.
The first two drugs he tried failed. But in April, Hassmann was switched to a drug called Campath-1H, made by a Cambridge, Mass., biotech company, LeukoSite. The drug worked like a ''smart bomb'' to knock out the cancer cells while sparing the marrow that makes new normal white cells. And unlike most standard chemotherapies, it didn't cause dangerous, toxic side effects.
''I was feeling better within a week,'' says Hassmann, astonished and grateful after a course of 12 weekly treatments. ''I came there with no hope. Now this could be good for many years.''
How long Hassman's new lease on life will continue is unknown. Like dozens of other novel anticancer agents that have prompted a surge of optimism in the field, Campath-1H is still in early testing.
What is clear, however, is that in 1998, there is marked optimism about this new generation of ''targeted'' therapies aimed at controlling cancer with vastly more precise and less toxic drugs than those now available.
''We've pushed [conventional] chemotherapy about as far as it can go,'' says Dr. John Mendelsohn, a molecular biologist and president of M.D. Anderson. ''It's possible we'll be able to discover new chemotherapy agents, but we think the targeting of oncogenes or tumor suppressor genes'' that malfunction in cancer cells ''is another major attack we can make'' on the disease.
The cancer center, one of the nation's two largest (the other is Memorial Sloan-Kettering in New York), houses 800 faculty scientists and treats 65,000 patients a year. There are 494 clinical trials in progress here, including a broad sampling of the novel cancer therapies that have moved into the spotlight in the last year.
Patients come to Houston from all over, many of them staying in high-rise hotels that loom over the enormous Texas Medical Center in which M.D. Anderson is located. In various clinics, they sit waiting for treatments, undergoing infusions of drugs through intravenous lines, or nervously anticipating lab results.
Some, like Hassmann, are receiving drugs based on monoclonal antibodies - engineered proteins that recognize and latch onto specific cancer cells. Other drugs are designed to block cancerous growth signals from reaching the receivers on the surface of cells or inside them - like filling a keyhole with gum so the key won't fit, as one researcher put it.
Others have volunteered for tests of angiogenesis inhibitors. These drugs disrupt the network of tiny blood vessels a tumor needs to grow, thus halting or shrinking the tumor. In early human testing these inhibitors have produced mixed results, but the most powerful ones are not yet ready for patient trials.
Still other patients, including some with lung, head, and neck cancers, are undergoing gene therapy. Dr. Jack Roth, chairman of thoracic surgery at M.D. Anderson, is leading trials in which a gene that is often defective in cancer cells, called P53, is being ferried into tumor cells by means of a virus, in hopes of halting malignant growth.
It is P53's job to detect cells with damaged DNA, and either keep them from dividing until they are repaired, or nudge them along a path to programmed self-destruction before they can do harm. Mutant P53 genes, by contrast, allow damaged cells to keep on reproducing, which can lead to cancer as the cells accumulate genetic damage.
''If you restore P53 function'' with gene therapy, ''it could trigger this cell death'' and turn off cancerous growth, Roth says. The therapy appears safe and has shown some activity against tumors in early tests, he adds.
Strategy takes aim
at broken cells
Another strategy aims not to repair cells with broken P53s, but to wipe them out. A bioengineered virus called ONYX-015 specifically attacks and kills cells with mutant P53 genes. Scientists reported this spring that in combination with two standard chemotherapy drugs, the virus has shrunk tumors of the head and neck in 9 out of 10 patients in early trials.
Cancer vaccines - the name for a strategy of revving up the immune system to attack cancer cells - are also being tested here and at a number of academic centers and biotech companies. Efforts to harness the immune system to fight cancer has had a long history and few real triumphs, but scientists now know more about how the complex immune defenses work and are more optimistic that selective and powerful vaccines can be made.
One vaccine that mobilizes the immune system against deadly melanoma is heading toward possible approval in Europe and Canada by the end of the year and perhaps next year in the United States. Called Melacine, it has been tested in patients with advanced melanoma who have dismal prognoses. It has proven to be as effective in extending survival by a few months as is the standard four-drug chemotherapy treatment. But Melacine is much less punishing in its side effects, say officials of RIBI ImmunoChem Research, Inc., the vaccine's makers.
In contrast to the broadly toxic chemotherapies in use today, the new agents have been precisely designed to attack, or in some cases, correct, specific genetic changes that turn normal cells into malignant ones.
''Up to now, we have cured a series of cancers that affect young people,'' says Dr. Donald Coffey, of the Johns Hopkins Cancer Center, referring to diseases like leukemia and Hodgkin's disease in which the war on cancer has had its greatest triumphs to date. ''We did this with drugs that blocked DNA synthesis'' - meaning they killed tumor cells, but often hammered normal cells as well, causing terrible side effects.
But now, scientists are developing drugs aimed at blocking the effects of mutant, cancer-causing oncogenes, restoring broken tumor-suppressor genes, and overcoming malfunctioning DNA-repair genes. They hope these therapies will bring outlaw cancer cells back into good behavior or prod irrevocably damaged cells into apoptosis, or cell suicide.
If conventional chemo is like bombing an entire city to kill off a guerrilla force, the newer drugs aim to pick off the enemy and spare the civilians.
''I've never seen so many ways to attack cancer,'' says Coffey. Indeed, a survey this year by an industry group showed that of 350 biotech drugs under development, 151 - more than one-third - target cancer. There were 30 for melanoma alone, 20 for colo-rectal cancer, and 13 each for prostate and breast cancers.
And, as reports at this spring's meeting of the American Society of Clinical Oncology reflected, the early tests of many of these agents are promising.
''I've never seen so many positive results in my life,'' says Dr. Dan Von Hoff, founder of ILEX Pharmaceuticals and an oncologist at the San Antonio Cancer Institute. ''The biology is beginning to pay off. Now you can sit down and look a patient in the eye and say there's a good chance of this doing you good.''
Despite a flurry of media reports this spring proclaiming that a cancer ''cure'' might be at hand, few scientists will touch that word. Sobered by decades of experience with cancer's Houdini-like ability to escape and survive, researchers say the new agents may realistically prove more successful at taming cancer than destroying it.
''We may have cures someday,'' says Samuel Waksal, president of ImClone Systems Inc. in New York, which is developing targeted cancer therapies, ''but the types of approaches we're developing now may make cancer a chronic disease. We would like to kill every cancer cell, but we're recognizing that if you can keep people alive for 30 more years, using drugs with few side effects - that's pretty dramatic.
''And,'' he adds, ''that's a goal that is achievable in the near term.'' Even in the next two or three years, ''the world [of cancer treatment] is going to change.''
For ethical reasons, the newest drugs are tried first in patients with hopelessly advanced cancer. Despite the grim odds, one such drug is already sparking a glimmer of hope for patients with aggressive, incurable brain tumors called glioblastomas. The drug, called SU101, blocks an overactive cell growth-signaling pathway in brain cells and has kept a few patients alive for one or two years. Under normal circumstances, they would have died within three months, says Dr. Eric Wong, a neuro-oncologist at Boston's Beth Israel Deaconess Medical Center, where the drug is about to begin testing.
Last month, Nelba MacMurdo, 66, of Canton, finished her first seven-week course of SU101: Her children had read about the experimental drug in a newsmagazine and sought out Wong. Whether it has affected the brain tumor whose tentacles couldn't be surgically removed wasn't immediately clear. But her daughter, Leslie, says she has experienced few side effects and has felt ''renewed zest just knowing there's something that could potentially help her.''
No one expects any of the new biological therapies, as effective as they may prove, to do the job alone. Most researchers believe they will work best when combined with other therapies and with standard chemotherapy drugs to attack the elusive cancer cell on many fronts.
''We don't have to hit a home run to cure people'' with newer agents, says Dr. Christopher Logothetis at M.D. Anderson. ''We just have to get a base hit, because we already have one with chemotherapy - this could give us a run batted in. That's why many of us are really optimistic that we're going to be able to change the course of this illness.''
For example, ImClone's cancer drug C225, based on an antibody discovery by Mendelsohn, is being tested in combination with radiation for head and neck cancers. The radiation damages the cell while the C225 antibody blocks a chemical growth factor, the EGF receptor, that the cell needs in order to divide. The one-two attack has proven successful in halting tumors in the early tests, says Mendelsohn.
If they are cautiously optimistic that the new era of rationally designed drugs and targeted therapies may yield major inroads into the disease, the researchers are also mindful of the potential pitfalls.
Normal cells in body tissues are of one kind, but cancer cells - even in the same tumor - are genetically diverse, points out Coffey at Johns Hopkins. ''Diversity allows cancer to survive'' by becoming resistant to drugs that attack just one type of cell, he says. ''Cancer is an evolutionary process that spins off variants you can't control.''
Angiogenesis inhibitors may get around this obstacle because they don't attack the cancer cell itself, only its blood supply, and the blood vessel cells that are the target don't develop resistance. In animal experiments, resistance to the angiogenesis agents has been remarkably absent.
Hurdles remain before
drugs reach market
But there are other hurdles. Turning experimental proteins from the laboratory into commercial-scale drugs is difficult. Many of the proteins are large, complex, and difficult to make. Genentech is building a new manufacturing plant to churn out a drug called Herceptin for what is expected to be a large market, once it gains FDA approval. But these scale-ups take time and effort. Moreover, large proteins need to be taken intravenously; the hope is to produce small molecules that patients can take orally.
Other researchers still labor to find better ways to test promising drugs in animals. Though scientists have worked for years to create mice that mimic human cancer, mice experiments still often don't predict what a drug will do in humans, and the search for still better animal models continues.
Says Dr. Martin Abeloff, director of the Johns Hopkins Cancer Center: ''We're all excited about the potential of really being able to attack this disease in a more scientifically-based approach. But we also have to be cautious, because we're learning about the complexity of these processes.''
And, he says, it's not as if cancer treatment is moving into a ''different universe.''
''I don't feel like what we've done in the past'' with conventional treatments will be rendered obsolete, he says. ''We'll never abandon them, even when we have the new biologically-based approaches... we'll use them together.''
Globe Online
This series is available
on the Globe Online at
http://www.boston.com. Use the
keyword: Cancer.
This story ran on page A01 of the Boston Globe on 08/03/98.
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