By February of last year, Victoria Reiter, 63, figured she had only a few months to live. A writer and translator living in Manhattan, she was suffering from chronic myeloid leukemia, an especially deadly form of blood cancer. The only treatment available was interferon, an immune-system booster that wasn't really working and that made her violently ill. Reiter had spent most of 1999 in bed, too sick to read, to walk, to do much of anything - although she had managed to put together lists dividing her possessions between her two daughters.
Then she went on an experimental drug called Gleevec, and within weeks everything changed. "All my energy started coming back," she says. "Suddenly I could read. I could take a walk." By August, tests showed her bone marrow was clear of leukemia cells; in December, she took up the Argentine tango. She still has the lists of what her daughters will get, but, she exults, "They're not going to get it yet!"
For Bob Ferber, a Los Angeles prosecutor specializing in animal-abuse cases, the Gleevec experience was very much the same. Less than two years ago, he was lying in a hospital room considering suicide to escape the pain radiating from his bones. "From crawling across the floor on my knees to go to the bathroom, I'm now back at work," says Ferber, 48. "I go to the gym. I'm volunteering for an animal-rescue group. I have a girlfriend. It's the dream of any cancer patient in the world to be able to take a pill that works like this. It's truly a miracle."
That's a tempting way to look at it, anyhow. Gleevec is effective enough that the U.S. Food and Drug Administration approved it in record time two weeks ago - even as researchers announced that it also works against a rare form of stomach cancer. The drug doesn't help everyone, and it can have side effects, including nausea, muscle cramps and skin rash. Moreover, nobody is claiming that it actually cures cancer. Patients may have to continue taking the drug, probably for the rest of their lives, and unless Gleevec is used in combination with some other drugs, it is likely their cancer will come back.
Despite all these caveats, Gleevec is still a breakthrough - not only for what it does but, more important, for the revolutionary strategy it represents. A full 30 years have passed since President Richard Nixon declared war on cancer and called for a national commitment comparable to the effort to land on the moon or split the atom. But over those three decades, researchers have come up with one potential miracle cure after another - only to suffer one disappointment after another. Aside from surgery, which almost invariably leaves behind some malignant cells, the standard treatment for most cancers continues to be radiation and chemotherapy - relatively crude disease-fighting weapons that have limited effectiveness and leave patients weak and nauseated.
Along the way, though, scientists have amassed a wealth of information about how cancer works at the molecular level, from its first awakening in the aberrant dna of a single cell's nucleus to its rapacious, all-out assault on the body. Armed with that information, they have been developing a broad array of weapons to attack the disease every step along the way. Many of these therapies are just beginning to reach clinical trials and won't be available to save lives for years to come. If you have cancer today, these treatments are likely to come too late to help you. But, says Dr. Larry Norton, a medical director at Memorial Sloan-Kettering Cancer Center in New York City: "I think there is no question that the war on cancer is winnable."
That sentiment was pounded home last week at the annual meeting of the American Society of Clinical Oncology in San Francisco, where a record 26,000 cancer specialists from around the world briefed each other on the good news starting to pour out of their laboratories. Unlike chemo and radiation, which use carpet-bombing tactics that destroy cancer cells and healthy cells alike, these new medicines are like a troop of snipers, firing on cancer cells alone and targeting their weakest links.
Some of these therapies prevent a class of chemicals called growth factors from reaching a tumor, blocking signals that would otherwise instruct the cell to grow out of control. Others tip the delicate balance that every cell maintains between life and death, driving cancerous cells to self-destruct. Still others block enzymes that cancer cells use to chew openings in normal tissues and give themselves room to expand. And, most famously, the class of compounds known as angiogenesis inhibitors keep tumors from building new blood vessels to supply themselves with food and oxygen. Three years ago, Nobel laureate James Watson, co-discoverer of the structure of dna, was quoted as saying Dr. Judah Folkman, the Harvard researcher, would use these inhibitors to "cure cancer within two years."
He later claimed that he had been misquoted - and no wonder. Scientists who know anything about cancer are exceedingly cautious about using the C word. That's partly because it too easily raises false hopes and partly because doctors are increasingly convinced that a cure is not the only way to beat cancer. Instead, experts believe, by throwing a series of monkey wrenches into the cancer cell's machinery, the new therapies could transform cancer from an intractable, frequently lethal illness to a chronic but manageable one akin to diabetes and high blood pressure. Says Dr. Leonard Saltz, a colon-cancer specialist at Memorial Sloan-Kettering: "I don't think we're going to hit home runs, but if we can get a series of line-drive singles going and put enough singles back to back, we can score runs."
Four years ago, for example, researchers at IDEC Pharmaceuticals in San Diego, Calif., hit just such a line-drive single with Rituxan, the first drug that successfully targeted proteins on cancer cells. Scientists had learned over the years that cancer cells are studded with an unusually large number of receptacles that compounds essential for survival, including growth factors, can plug into and fuel the cells' growth. Rituxan is a monoclonal antibody, a molecule specifically engineered to fit into the receptacles on non-Hodgkin's lymphoma cells and, in this case, single out the cancer cell for destruction by the immune system. Back in the early 1980s, monoclonal antibodies were hyped in the media as "magic bullets" that would wipe out cancer.
That proved far too strong a claim, but monoclonal antibodies have finally begun to live up to more modest expectations. Rituxan was the first, but just a year later, the same approach led to Herceptin, a drug that keeps growth factors from feeding certain kinds of breast-cancer cells. Such targeted treatments are effective only when the appropriate target exists. Herceptin, for example, latches onto a receptor known as her2, which is abnormally abundant in only about 30% of breast-cancer tumors. A biopsy can tell doctors whether a patient is likely to respond to Herceptin, but they'd hoped to find a molecule that would plug into a growth-factor receptor more prevalent in cancer cells.
Sure enough, they found one. Dr. John Mendelsohn, then at the University of California, San Diego, and now president of the M.D. Anderson Cancer Center in Houston, had been focusing since 1981 on a receptor called egfr, which is host to a protein called epidermal growth factor (EGF). It's a close cousin to her2, and Mendelsohn and his team know that it is present in a huge variety of tumors; two-thirds of all cancer types, in fact, are blanketed with EGF receptors. In 1984 Mendelsohn and his team showed in mice that blocking the EGF receptor with a growth-factor decoy prevented a cell from growing and dividing.
Making a drug out of that decoy would prove tricky, since the receptor, like her2, also shows up on noncancerous cells. Researchers are now learning, however, that normal cells are more adept than cancer cells at finding other growth factors on which to rely when EGFR is blocked. But when Mendelsohn applied for his first grant from the National Cancer Institute in 1983, he was rejected. "Nobody thought it would work," he says. The following year he turned to philanthropic sources for research dollars. Last year he wowed colleagues with a compound called imc-c225, which proved effective in treating colon tumors in a small number of patients.
Then just this year researchers at Sloan-Kettering showed that the drug could dramatically boost the effectiveness of standard colorectal-cancer chemotherapy, shrinking tumors in more than a fifth of otherwise hopeless cases. Says Sloan-Kettering's Saltz: "The fact that we got a 20% response rate is staggering." What is happening, he surmises, is that the growth-factor inhibitor weakens the tumor enough for chemotherapy to finish it off.
Buoyed by those results, Saltz will begin testing imc-c225 in less advanced patients this summer. And because combination therapy seemed to work so well, he is combining the EGFR inhibitor with not one but two chemotherapy agents to pack a triple punch.
Those are only two drugs that keep EGF from doing its job. Gleevec, which reversed Reiter's and Ferber's leukemia so dramatically, is another; so is Tarceva, a drug from OSI Pharmaceuticals in Uniondale, N.Y., which is showing promise against some lung tumors as well as head and neck cancers. Neither of these compounds keeps EGF from docking with cells; instead, each worms its way inside the cells, where it intercepts growth messages percolating in from the surface. Astra Zeneca, headquartered in London, is testing a similar compound, Iressa, against some lung, stomach and prostate cancers.
And that's just the start. Gleevec, Tarceva and Iressa all break one of the most common signaling pathways by blocking an enzyme known as a tyrosine kinase. But the message that encourages a cancer cell to grow involves hundreds of biochemical signals that can travel by hundreds of different pathways. Each of those pathways represents a target, a link that could be interrupted with the properly designed drug.