IMCL news from the Chicago Tribune:
chicagotribune.com
'Smart-bomb' drugs transform cancer war
Hopeful researchers predict a treatment explosion
Related links
CancerNet. Information from the National Cancer Institute. (These links will take you out of chicagotribune.com)
"How Cancer Arises." A September 1996 article from Scientific American magazine on the molecular underpinnings of cancer.
ImClone Systems Inc.
International Classification of Diseases.
Lombardi Cancer Center.
Memorial Sloan-Kettering Cancer Center.
Oncology.com. Online cancer news and information. Registration required.
University of Colorado Cancer Center.
By John Crewdson
and Judy Peres
Tribune Staff Writers
February 27, 2000
After decades of frustration, false starts and dead ends in the desperate struggle to save the half-million Americans who die each year of cancer, effective new treatments may at last lie within reach for many patients with previously intractable cancers.
The new treatments, "smart-bomb" drugs designed to seek out and destroy cancer cells while leaving normal cells unharmed, are still in their infancy, and the number of patients in whom they are being tested is small.
But researchers around the world are reporting case after case in which men, women and children who were expected to die are not only still alive but in some cases cancer-free.
"There has been a series of events that you could call inspirational in terms of their impact," says Dr. Marc Lippman, who directs the Lombardi Cancer Center at Georgetown University in Washington, D.C.
Dr. Paul Bunn, a veteran cancer researcher and chief of the University of Colorado Cancer Center in Denver, equates what is happening in cancer research with the advent of antibiotics to treat infectious diseases. "All these things are more exciting than anything we ever had," Bunn says.
To be sure, cancer researchers have been excited before: about interferon, about interleukin-2, about tumor necrosis factor, about monoclonal antibodies, each of which was portrayed in the popular press as a "magic bullet."
As the world now knows, none of those bullets hit its target. But the hope of the moment is occasioned not by a potential new drug, or even a new mode of treatment. Rather, it is the recognition that vast new insights into how cancer cells behave, accumulated over 20 years of advances in molecular biology, have opened avenues of attack previously undreamed of.
"For years in oncology, you looked at a cancer cell and it's like 'Mission Impossible,' when you open up the bomb and you see a green wire, a red wire, a blue wire and all these lights," says Dr. Samuel Waksal, a former National Cancer Institute researcher whose company, ImClone Systems, has parlayed the new technology into several prospective drugs. "You'd take a sledge hammer and try to smash it. If you were lucky, you could destroy the tumor without blowing up the patient. Now we actually know what the blue wire does and what the green wire does. Now we can clip one wire, and do it in a very specific fashion."
The new drugs do not spell the end for current cancer therapies, at least in the foreseeable future. Surgeons and radiologists continue to refine their techniques; the latest wrinkle in radiotherapy, intensity modulation, has recently become available at the University of Chicago and a few other cancer centers.
Tumors that are detected early enough will still be treated with traditional methods, though with the addition of new drugs to eliminate any tumor cells left behind. Several of the new drugs, moreover, appear to be more effective in treating advanced cancers when combined with standard chemotherapy.
What oncologists now dare to hope is that the addition of tumor-targeted drugs to their arsenal may at last overcome the cancers they cannot kill with existing treatments.
'A whole new way'
To Dr. Michael Gruber, chief of neuro-oncology at the New York University Medical center, the current transformation marks "the beginning of a whole new way of treating cancer." Jean-Claude Horiot, president of Europe's largest cancer research organization, talks of an impending "earthquake" in cancer treatment, whose "tremors are already being felt."
What amounts to a revolution in cancer treatment is happening quickly and quietly, mostly without press conferences or headlines, although that will change in the spring, when thousands of cancer researchers gather in San Francisco and New Orleans to share the results of scores of ongoing studies.
According to Dr. David Golde, physician-in-chief at New York's Memorial Sloan-Kettering Cancer Center, the revolution has been enabled by "an enormous amount of basic biomedical, biologic and biochemical information" about how cancer happens, a succession of incremental advances that have accumulated "at a really striking rate."
Such discoveries now occur weekly, mostly in university laboratories and small biotech companies, often founded by the researchers who made those discoveries.
Companies with promising treatments quickly become candidates for lucrative stock offerings or takeovers by giant pharmaceutical companies keen to cash in on the breakthrough. Wall Street's ardor is reflected in last year's 71 percent rise in the Dow Jones Biotechnology Index, half of which occurred during the last three months of the year.
Cancer researchers say the involvement of companies is crucial, because no university has the money needed to test a prospective drug on a succession of patient volunteers, a process that takes years and millions of dollars.
Though the new treatments employ a variety of sophisticated approaches, all share the elusive goal sought by researchers for decades -- singling out malignant tumor cells and reducing them to a harmless mass of pus, while leaving healthy cells alone.
The path now being taken would have been impassable only a few years ago: using computers to design specialized molecules that disrupt cancer cells' internal and external communications, jam their reproductive machinery, cut off their blood and oxygen supplies, send them bogus "self-destruct" messages, even turn the body's natural immune defenses against them.
Fears of false hope
Researchers worry most about giving patients false hope, and they are unanimous in cautioning that, for a variety of reasons, preliminary drug trials in patients who often are desperately ill and have not been helped by previous treatments are not necessarily indicative of a drug's ultimate success or failure.
Still, they find it difficult to contain their excitement over a new drug, STI 571, which at high doses produced complete remissions in 31 of 31 patients with chronic myelogenous leukemia (CML). Dr. Steven T. Rosen, director of Northwestern University's Robert H. Lurie Comprehensive Cancer Center, calls STI 571 "a home run," a term rarely heard in cancer research.
Many of the drugs in use today are substances discovered in nature that happen to kill cancer cells, usually by interfering with their ability to divide and multiply. One widely prescribed drug, Taxol, comes from the bark of the Pacific yew. Another popular chemotherapeutic, etoposide, is an extract of the May apple plant.
It is the process of their discovery that distinguishes the new drugs from their predecessors.
"This is not some leaf from the Amazon," says Georgetown's Lippman of STI 571. "This is no longer just grinding up tumors and throwing in a little eye of newt, and hoping for the patient to throw away their crutches and walk. This is, 'Let's figure out what causes CML, let's now rationally design a drug that goes after that.' And it works."
Nearly as impressive is another targeted therapeutic, ImClone's C225, which combined with radiation eliminated head and neck cancers in 15 of 23 patients who previously failed to respond to chemotherapy and shrank tumors dramatically in seven others. Most of those remissions have persisted for nearly two years, well beyond what would be expected with standard treatments.
On Monday, researchers in Germany will report an immune-stimulating "vaccine" for advanced kidney cancer that is producing nearly 50 percent response rates and complete remissions in a quarter of patients treated, compared with 20 percent response and 10 percent survival with existing treatments.
Not every new drug is a home run. But a number are racking up complete and partial remissions in a third to a half of the cancer patients in whom they are being tested. Already several companies, large and small, are in pursuit of cancer's Holy Grail: a pill that can prevent cancer before it happens.
A popular arthritis drug, Celebrex, recently was approved by the U.S. Food and Drug Administration for the prevention of precancerous polyps that lead to an inherited form of colon cancer. FDA approval is pending for another drug, Aptosyn, that does the same thing in a different way. The makers of both drugs plan to test them soon in other cancers.
The need for better cancer treatments is so urgent because current drugs simply do not work in many patients with advanced cancers.
"Have you ever noticed," asks Northwestern University's Dr. Gerald Soff, "that when oncologists give a treatment to a patient, and the cancer grows or the patient dies, we say the patient failed the treatment? We failed. The drugs failed. We failed the patient."
Harvard University's Dr. William Kaelin puts it even more bluntly, observing that current treatment for breast, lung and colon cancer, the three major killers, "remains abysmal for patients whose disease cannot be controlled by surgery." Indeed, three decades after the nation declared war on cancer, there is still a 40 percent chance that an American will contract some form of cancer, and a 20 percent chance that he or she will die from it.
Remaining obstacles
The principal obstacle to effective treatment has been that rapidly dividing cancer cells too often develop immunity to traditional cancer drugs. A second problem is that most current chemotherapeutics don't discriminate between cancer cells and other cells that must reproduce as part of the body's normal function: hair follicles, for example, or the cells that line the mouth, stomach, uterus and colon, or inhabit the bone marrow.
That's why so many cancer patients lose their hair, suffer nausea, vomiting, diarrhea and reduced immunity to disease, even damage to the heart and other vital organs. "The patients it doesn't help, it obviously hurts," says the NCI's Dr. Steven Rosenberg.
One cancer drug still in general use, cyclophosphamide, was developed in the 1950s. Two other standard drugs, doxorubicin and 5-FU, have been around for decades. Even mechlorethamine, a derivative of World War I-era mustard gas, is still prescribed for some cancers.
"Those treatments were designed in an era when we didn't really have any concept of what made cancer cells work," says the NCI's Dr. Edward Sausville, who is in charge of developing new cancer treatments.
"We now have insights into what makes cancer successful, so it's time to evolve away from those treatments that were modestly effective in some situations, truly effective in a few situations, and ineffective in a number of areas."
April 12, 1955, the day Jonas Salk announced the discovery of a vaccine that prevented polio, was a time of national celebration. No one believes any longer there will ever be a breakthrough cancer cure that is announced on the evening news and in banner newspaper headlines.
The recognition that there are hundreds of kinds of cancer -- lung cancer alone is a collection of more than a dozen distinct diseases, and the International Classification of Diseases lists more than 30 lymphomas and more than 50 leukemias -- has led to the realization that victory over cancer, if it comes, will present itself as many smaller victories over many different cancers.
"We haven't had a key cancer fall yet, one of the biggies," says Sloan-Kettering's Golde, referring to the lung, breast, colon and prostate cancers that are collectively the biggest killers. "But we will."
Breakthrough predictions were also heard in the 1970s, when the federal government spent more than $50 million developing interferon, initially presented as a panacea for cancer, then dismissed as a disappointment when it failed to help many patients.
Now interferon is back in what oncologists call the "cancer armamentarium," thanks to a vastly improved understanding of how it works. Doctors at Massachusetts General Hospital in Boston recently reported using interferon to successfully treat a tumor in the jaw of a 5-year-old girl.
"She can smile again," says Dr. Judah Folkman, the Harvard researcher who demonstrated that interferon, rather than attacking the tumor directly, can be used to shut down a tumor's supply of life-giving blood.
The "magic bullets" of the 1980s were monoclonal antibodies, molecules designed to home in and destroy a particular kind of cancer cell, and which the NCI incorrectly predicted would "save tens of thousands of lives" before the end of that decade.
The first monoclonals were from mice. Even when they worked, the patients to whom they were given developed toxic reactions, and they didn't often work. "They had hoped that a monoclonal would just attach to a cancer cell and kill it," Golde says. "I don't know why they thought that."
Many more strategies
Since then scientists have figured out how to "humanize" mouse antibodies and how to identify appropriate targets on cancer cells. "You have to have the right target," Golde says, "and you have to have the right antibody, and that wasn't appreciated early on. There are many strategies now."
Rituxan, the first monoclonal antibody approved by the FDA for cancer treatment, is designed to target a specific blood cell cancer. In studies, Rituxan shrinks tumors by at least 50 percent in half the test subjects. Last year sales reached $280 million, and Rituxan is now being tested in other cancers. Northwestern's Rosen calls it "another home run."
The second monoclonal approved by the FDA for cancer therapy was Herceptin, which extends the lives of women with a less-common form of breast cancer by 25 percent when combined with chemotherapy. The makers of Panorex, a monoclonal antibody used to treat advanced colon cancer in Germany but not yet approved in the U.S., say it has reduced deaths in test patients by a third after seven years.
Even more intriguing to researchers are monoclonal antibodies combined with tiny radioactive molecules, which deliver cell-killing radiation directly to the tumor. One of the first, Bexxar, has reduced tumors by more than half in 100 percent of lymphoma patients treated.
The molecular revolution in cancer treatment dates back to the discovery, more than a half-century ago, that the essence of life is embodied in a mundane chemical called DNA; the genetic blueprint for a human being requires 3 billion tiny DNA molecules, joined in a cleverly folded strand that measures 3 feet in length.
The mystery of how genetic information is transmitted from cell to cell, and ultimately from parent to offspring, was answered in 1953 by Francis Crick, a Cambridge University physicist turned biologist, and a young graduate student, James Watson, who presented their revelation in a 900-word letter to the British scientific journal Nature.
Accompanying the letter was a crude drawing of two strands of DNA wound one around the other in what is universally recognized today as the Double Helix.
As a cell divides to form two identical cells, the Double Helix unwinds. With the help of enzymes, each strand of DNA makes a copy of itself. When the four strands recombine, both of the new cells have a Double Helix of their own.
"The whole business was like a child's toy that you could buy at the dime store," the German physicist Max Delbruck once remarked. "All built in this wonderful way that you could explain in Life magazine so that really a 5-year-old can understand what's going on. That there was so simple a trick behind it. This was the greatest surprise for everyone."
In one of the understatements of all time, the Crick-Watson letter observed, "It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material."
Perhaps without fully realizing it, Watson and Crick also had described the mechanics of cancer, in which a single cell, having done its job perfectly for decades, begins to reproduce with abandon. One cell becomes two, two become four and -- after six months or a year or 10 years -- a few billion cells become a tumor.
With the secrets of the Double Helix laid bare, researchers in the 1960s and 1970s focused on the much more complex, and interesting, question of how cells control life and death by enabling the manufacture of proteins according to specific sets of instructions, called genes, written in the lingo of DNA.
The first clue to how cancer happens arrived in the mid-1970s, when it was learned that humans possessed a gene nearly identical to a gene that causes cancer in chickens.
All that stood between the normal cell and cancer, it now seemed, was a tiny difference in their DNAs, a typographical error that transforms a normal gene into a malignant one.
Such an error could be inherited. Or, it could result from decades of exposure to some carcinogen -- cigarette smoke or sunlight or asbestos, even a viruslike hepatitis or papilloma, which have been linked to liver and cervical cancers.
Whatever the trigger, the recognition that humans carry the seeds of cancer within their own genes changed the course of cancer research and paved the way for the discoveries now unfolding.
Imagine a cell as a factory filled with thousands of machines and with hundreds of antennas on the roof, each tuned to send and receive chemical messages at a particular frequency.
Except for cells that require frequent replacement or are needed to heal a wound, in most healthy cells the machines are usually resting, occasionally switching on and off to tidy things up in response to biochemical instructions picked up by the surface antennas.
In a cancer cell something has gone haywire. Perhaps a gene whose normal function is to regulate housekeeping has acquired a DNA mutation and begins sending the cell a steady stream of unauthorized messages to divide and multiply.
Perhaps the culprit is a "tumor-suppressor" gene whose normal function is to hold the cell in check but which has been damaged in some way and can no longer do its job.
Perhaps the cell's antennas are picking up bogus instructions from nearby cells intent on fomenting a revolt. Perhaps the cell's own genes are misinterpreting innocuous signals as commands to reproduce.
Current treatment with cancer drugs resembles high-altitude carpet bombing. Many cancer cells are destroyed in those indiscriminate attacks, but so are normal cells the body needs to function. And, because some cancer cells usually survive the raids, tumors that shrink too often grow back, and patients die.
In the years since those drugs were developed, science has learned how to clone, or copy, cellular genes, and how to amplify, study, deconstruct and synthesize the myriad kinds of proteins -- enzymes, growth factors, biochemical signals, cell-surface receptors and more -- for which the genes hold the code.
That done, researchers began listening in on communications between cells, sorting out innocuous messages from those that signal the beginnings of cancer.
The result is targeted drugs that behave more like cruise missiles, sparing surrounding neighborhoods while seeking out cancer cells.
Because they are surgically precise, such drugs confer relatively few toxic side effects -- an advantage when those drugs are eventually combined with existing therapies, as most researchers expect they will be, and an enormous boon if the day comes when they are used alone.
Equally enticing is the fact that several of the newest drugs can be taken orally.
Assuming they work, that will eliminate the current need for patients to visit hospitals or chemotherapy centers several times a week, and bring state-of-the art cancer treatment as close as every drugstore.
No one can say how soon miracles will happen, if they happen at all. What can be said is that, for the first time, patients who were expected to die -- of blood cell cancers, of head and neck cancers, of kidney cancers, of colon cancers, even of lung cancers -- are alive and well, spending time with the husbands, wives and children who, in many cases, had been planning their funerals.
Georgetown's Lippman calls the new drugs "the tip of the iceberg.
"I'm not suggesting that every cancer patient is now assured a cure," Lippman says. "But I do think if you say, 'What is the thought process behind these agents versus the process behind those agents we were using in the clinic five years ago,' there's no comparison." |
