When future historians look back, they may well divide the nation’s protracted War on Cancer into the years before and after STI 571.
For decades, cancer researchers have become adept at putting the best face on less than spectacular results. “Most people think that if you have a cancer treatment which will improve survival by two months, that that’s a step forward,” says the University of Colorado’s Dr. Paul Bunn.
But that was before STI 571, an orange capsule that has allowed its chief investigator, Dr. Brian Druker, to claim what no cancer researcher has before: complete remission in 100 percent of patients.
Granted, the study participants all suffered from a relatively rare form of leukemia, a cancer of the white blood cells, and their disease was not in the most advanced stages. Nevertheless, once the right dose was found, 31 of 31 patients were able to reclaim the lives they had before they were diagnosed with cancer.
Now many scientists in many labs are in pursuit of tumor-killing molecules like STI 571. Scores of drugs, employing a variety of different mechanisms, already are being tested in patients.
But STI 571 is the first to prove the principle that underlies the current revolution in approaches to cancer therapy, and it may represent a blueprint for the conquest of many different cancers:
Discover what makes the cells of a particular cancer different from all other cells. Then design a molecule that seeks them out and kills them, or at least keeps them from multiplying–in the case of STI 571, by blocking a specific protein found only in leukemia patients.
“The number of new approaches that are truly targeted is just exploding,” says Dr. Drew Pardoll of Johns Hopkins Oncology Center, who is developing potential vaccines for cancer treatment.
The excitement expressed by researchers across the country is the result of a deepening understanding of the way cells work–how they communicate and why they sometimes malfunction.
All cells employ the same biochemical processes to grow and divide. In healthy adults, the growth of normal cells is so exquisitely regulated that cells reproduce just fast enough to replace dying ones.
The life cycle of the cell is governed not only by external signals–growth factors, for example–that tell the cell when to divide, but also by internal signals that tell it to commit suicide when something goes wrong: a viral infection, say, or a genetic mutation.
What makes cancer cells different is they can’t die.
“They’re either like a car that has a stuck accelerator–they grow without stopping,” says Druker, an oncologist at Oregon Health Sciences University in Portland. “Or their brakes don’t work, so they can’t shut off the growth.”
There’s increasing evidence that both characteristics probably exist in most cancers, along with two other traits: In order to become malignant, cancers need to be able to grow new blood vessels, so they can continue receiving oxygen and nutrients. And they must have the ability to invade surrounding tissues and to metastasize–spread to other organs in the body. Without the last two properties, cancers would never grow bigger than a BB and would rarely be life-threatening.
Scientists seeking to halt cancer in its tracks can try to interfere with any of those processes. But their attention is increasingly focused on the intricate biochemical circuits that cells use to relay the signals to grow or stop growing, to survive or die.
As molecular biology uncovers a burgeoning array of proteins that make up the signaling pathways, and the genes that encode these proteins, the number of potential targets grows apace.
The protein blocked by STI 571, bcr-abl, is only one of hundreds of molecules that relay growth signals within the cell and help regulate its reproductive cycle. Other molecules, called receptors, dot the cell surface like antennas to receive signals from outside the cell.
Signal interference
“We now have a much better understanding of the signaling network,” says Dr. Walter Stadler, a researcher at the University of Chicago. “And there are a number of (drugs) out there that inhibit one or more of the molecules in that network.”
Dr. Gary Schwartz, a researcher at Memorial Sloan-Kettering Cancer Center in New York, has been looking at drugs that block certain molecules, called kinases, needed for the cell to progress through its life cycle.
“Cell survival is based on a series of integrated circuits,” he explains. “For the cell to move from one stage of its life cycle to the next, proteins have to be activated like transformers in an electrical grid. If the protein-signals are blocked–it’s like interrupting an electrical circuit. The cell can no longer function or survive.”
But cells also have circuits that transmit death signals. “There’s a constant battle within the cell between signals that lead to life and those that lead to death,” says Schwartz.
In a healthy cell, all the circuits are operational, and the proper balance is maintained. In cancerous cells, the death signals are shut off because of some missing or deficient transformers. So the life signals gain the upper hand, and the cells grow out of control.
That suggests two possible fixes. “You can direct a drug to inhibit the life signals, so the death signals become paramount,” says Schwartz, “or you could activate the death circuitry.”
Many scientists are beginning to conclude that it will take combinations of drugs to make a real dent in cancer. A drug that blocks life signals may have to be combined with one that reactivates death signals. And both of those may have to be combined with chemotherapy.
Schwartz believes the faulty death circuitry in cancer cells is the reason chemotherapy is often ineffective. A toxic drug, or a blast of radiation, should initiate a death signal. But if the pathway isn’t working, the signal can’t get through. “The tumor cell doesn’t have the mechanism in place to allow it to die,” he says.
So giving chemo or radiotherapy along with a drug that can reactivate death signals appears to yield a one-two punch: One fixes the circuit while the other inflicts enough damage to turn it on.
“When you give some of these new drugs with chemotherapy or radiation,” Schwartz says, “they could be gangbusters.”
One that has caught researchers’ attention is C225, a synthetic antibody from ImClone Systems that made cancers of the head and neck disappear in 15 of 23 patients when combined with radiation or chemotherapy, and shrink significantly in seven others. (The last patient remained stable.)
When such cancers are treated in the traditional way, with radiation alone, between 30 percent and 40 percent of patients go into remissions that last an average of six months. But with C225 thrown in, 75 percent of the patients whose tumors disappeared were still cancer-free an average of 14 months after treatment.
“We’ve got patients now that are well over two years with complete regression of their cancers,” says ImClone’s president and CEO, Dr. Samuel Waksal.
Multiple approaches
Cell portals, or receptors, which may be produced in excess by tumor cells, represent another target for cancer researchers. If the portals are blocked, growth signals can’t reach the cell’s interior machinery.
The pharmaceutical giant AstraZeneca has a molecule, Iressa, that blocks a portal that appears in great numbers on the surface of about 30 percent of all cancer cells. In an early trial, Iressa caused tumors to shrink or stop growing in 14 out of 64 patients with a variety of advanced tumors. The response rate was even higher in lung cancer patients: 4 of 16 saw significant reduction in the size of their tumors, and two others remained stable.
“I don’t know if it’s the hit yet in lung cancer,” says Dr. David Golde, Sloan-Kettering’s physician-in-chief. “But it sounds to me like–what did Winston Churchill say?–it’s the beginning of the end. It looks like that and maybe some other things are about to make an impact.”
Two other synthetic antibodies, also known as monoclonals, already have been approved for cancer by the U.S. Food and Drug Administration. Herceptin is used to treat breast cancers that have an overabundance of a receptor known as HER2, and Rituxan is used to treat a form of non-Hodgkin’s lymphoma, a blood-related cancer.
Such monoclonals are designed to block the signals that tell cancer cells to reproduce. But because they are antibodies, they can also rouse the body’s immune system to attack those tumor cells with some of the same weapons used to defeat an invading virus.
In the latest refinement of this technology, a number of pharmaceutical companies are synthesizing cancer antibodies not for their immune-stimulating properties but as delivery systems–molecular messengers that send packets of toxic drugs or radiation directly to the tumor cell.
Despite impressive gains, some researchers see monoclonal antibodies as an approach that’s already being overtaken.
“Monoclonals are large proteins and are hard to make,” says Dr. Mark Kris of Sloan-Kettering. “When injected, they often cause fever and flulike symptoms. It would be nice to have a drug that’s easier to take and cheaper to make.”
What researchers call small-molecule drugs fit that description. “More people could be treated more easily–that’s the promise of small molecules,” Kris says.
The story of STI 571
That promise led Brian Druker to STI 571, the small molecule that may chart the future of cancer research. Druker, the Portland researcher, had been looking for ways to treat chronic myelogenous leukemia (CML)–a blood cancer characterized by skyrocketing white blood cell counts–since 1993.
After curing mice in his lab, he took the most promising compound into a trial with human subjects in 1998. Druker soon noticed that patients who were receiving even relatively low doses of the drug were showing relatively dramatic improvements in their blood counts.
At first Druker dismissed those observations as merely “interesting,” because the patients who improved weren’t particularly difficult cases. Then came a woman who was considerably sicker; her white blood cell count shot up to more than 10 times normal when Druker took her off her previous medication in preparation for the trial.
A week into the experimental treatment, her white count started coming down. Within three weeks it was normal.
“At this point,” Druker recalls, “I knew we had something important.”
One of Druker’s patients is Norma Bidelman, 54, of northwest suburban Hoffman Estates. Bidelman couldn’t take interferon, the standard treatment for chronic myelogenous leukemia, and she was too weak for a bone marrow transplant. She told her family her life wasn’t worth living.
Then, last August, she gained a place in Druker’s trial of STI 571. When Bidelman returned home from Portland in October, she felt good again. Now, she says, “I can start thinking about the possibility of getting on with my life.”
Douglas Jenson’s testimony is even more glowing. Jenson, 66, of Hood River, Ore., says he had lost 60 pounds after being diagnosed with CML. “I got to the point where I’d come down and sit on the porch. I’d watch the thermometer go up and come back down. Then I’d go back to bed.”
STI 571, he says, reinvigorated him.
“One of the miracles of this thing is the quality of life,” says Jenson, who started on the drug of April 1999. “I do cabinet work. I garden. I spend 45 minutes a day on my Exercycle. Last summer I completely rebuilt my deck and remodeled the back end of the house.”
All patients in the trial are monitored regularly for signs of damage to their vital organs and other side effects. But, so far, the only problem detected has been mild nausea.
STI 571 is now in second-round trials at Northwestern University Medical School and other sites around the country. The University of Chicago is set to start testing it in April.
Dr. David Parkinson, vice president for clinical research at Novartis, says the drug will be tested in children, in adult patients at different stages of CML, and in other leukemia patients. It may also be tried on a number of other cancers.
One of the reasons CML–a relatively rare leukemia that hits about 5,000 Americans a year–is among the first cancers to yield to a targeted therapy is that it appears to be caused by a single genetic mutation, the so-called Philadelphia chromosome.
But most cancers involve multiple genetic abnormalities. “So most likely we’ll end up, not with a silver bullet, but with many separate silver bullets,” Druker says. “And you may have to use them in combination, because you’ll have to shut down all the abnormalities.”
Nearly 40 years elapsed between the identification of the Philadelphia chromosome and the advent of STI 571. But new drugs can be developed much faster now that the scientific foundations for charting genetic abnormalities have been laid.
The process of reading and decoding the language of DNA, expensive and time-consuming even 10 years ago, has since been automated. Powerful computers allow researchers to screen enormous “libraries” of chemical compounds and to generate “designer” drugs.
The National Cancer Institute’s Dr. Edward Sausville thinks the big question with drugs that affect signaling is whether patients will be able to take them safely over a long period.
Those and other unknowns lie ahead, and researchers caution against drawing conclusions from the results of early studies.
“To be honest,” says Johns Hopkins’ Pardoll, “it’s going to take five more years to see how these things play out. The most promising agents haven’t been in the clinic long enough to see what they can do.”
Dr. Judith Karp, a cancer researcher at the University of Maryland, adds another caveat.
“We know what these new agents do in a test tube, to some degree, but we’re only just beginning to understand how they affect the human being as a whole entity,” she says. “We’ve got that to learn. And we also have to learn what these things will do when we combine them with other types of drugs.
“It’s really a brave new world out there.”
