We Fought Cancer…And Cancer Won.

A widely discussed 2004 article in Fortune magazine ("Why We're Losing the War on Cancer") laid the blame for this at the little pawed feet of lab mice and rats, and indeed there is a lot to criticize about animal studies. The basic approach, beginning in the 1970s, was to grow human cancer cells in a lab dish, transplant them into a mouse whose immune system had been tweaked to not reject them, throw experimental drugs at them and see what happened. Unfortunately, few of the successes in mice are relevant to people. "Animals don't reflect the reality of cancer in humans," says Fran Visco, who was diagnosed with breast cancer in 1987 and four years later founded the National Breast Cancer Coalition, an advocacy group. "We cure cancer in animals all the time, but not in people." Even scientists who have used animal models to make signal contributions to cancer treatment agree. "Far more than anything else," says Robert Weinberg of MIT, the lack of good animal models "has become the rate-limiting step in cancer research."

For this story, NEWSWEEK combed through three decades of high-profile successes in mice for clues to why the mice lived and the people died. Two examples make the point. Scientists were tremendously excited when Weinberg and colleagues discovered the first cancer-causing gene (called ras) in humans, in 1982. It seemed obvious that preventing ras from functioning should roll back cancer. In this decade, scientists therefore began testing drugs, called FTIs, that do exactly that. When FTIs were tested on human cancers that had been implanted into mice, they beat back the cancer. But in people, the drugs failed. One reason, scientists suspect, is that the transplanted cancers came from tumors that had been growing in lab dishes for years, long enough to accumulate countless malignant genes in addition to ras. Disabling ras but leaving those other mutations free to stoke proliferation was like using a sniper to pick off one soldier in an invading platoon: the rest of the platoon marches on. That general principle—not even the malignancy in a single cancer has one cause—would haunt cancer research and treatment for years. A compound called TNF, for tumor necrosis factor, raised hopes in the 1980s that it would live up to its name. When it was injected into mice carrying human tumors, it seemed to melt them away. But in clinical trials, it had little effect on the cancer. "Animal models have not been very predictive of how well drugs would do in people," says oncologist Paul Bunn, who leads the International Society for the Study of Lung Cancer. "We put a human tumor under the mouse's skin, and that microenvironment doesn't reflect a person's—the blood vessels, inflammatory cells or cells of the immune system," all of which affect prognosis and survival.

If mouse models have a single Achilles' heel, it is that the human tumors that scientists transplant into them, and then attack with their weapon du jour, almost never metastasize. Even in the 1970s there was clear evidence—in people—of the deadly role played by cells that break off from the original tumor: women given chemo to mop up any invisible malignant cells left behind after breast surgery survived longer without the cancer's showing up in their bones or other organs, and longer, period, than women who did not receive such "adjuvant" therapy, scientists reported in 1975. "Every study of adjuvant therapy shows it works because it kills metastatic cells even when it appears the tumor is only in the breast or in the first level of lymph nodes," says the ACS's Brawley. By the mid-1990s studies had shown similar results for colon cancer: even when surgeons said they'd "got it all," patients who received chemo lived longer and their cancer did not return for more years.

Yet for years, despite the clear threat posed by metastatic cells, which we now know are responsible for 90 percent of all cancer deaths, the war on cancer ignored them. Scientists continued to rely on animal models where metastasis didn't even occur. Throughout the 1980s and 1990s, says Visco, "researchers drilled down deeper and deeper into the disease," looking for ever-more-detailed molecular mechanisms behind the initiation of cancer, "instead of looking up and asking really big questions, like why cancer metastasizes, which might help patients sooner."

There was another way. At the same time that molecular biologists were taking the glamorous, "look for the cool molecular pathway," cojones-fueled approach to seeking a cure, pediatric oncologists took a different path. Pediatric cancer had long been a death sentence: in Farber's day, children with leukemia rarely survived more than three months. (President Bush's sister Robin died of the disease in 1953; she was 3.) Fast-forward to 2008: 80 percent of children with cancer survive well into adulthood.

To achieve that success, pediatric oncologists collaborated to such a degree that at times 80 percent of the children with a particular cancer were enrolled in a clinical trial testing a new therapy. In adults, it has long been less than 1 percent. The researchers focused hardly at all on discovering new molecular pathways and new drugs. Instead, they threw everything into the existing medicine chest at the problem, tinkering with drug doses and combinations and sequencing and timing. "We were learning how to better use the drugs we had," says pediatric oncologist Lisa Diller of Dana-Farber Cancer Institute and Children's Hospital Boston. By 1994, combinations of four drugs kept 75 percent of childhood leukemia patients—and 95 percent of those enrolled in a study—cancer-free. Childhood brain cancer has been harder to tame, but while 10 percent of kids survived it in the 1970s, today 45 percent do—a greater improvement than in most adult cancers. (To be sure, some scientists who work on adult cancers are sick of hearing about the noble cooperation of their pediatric colleagues. Childhood cancers, especially leukemias, are simpler cancers, they say, often characterized by a single mutation, and that's why the cure rate has soared. Neutral observers say it's a little of both: pediatric-cancer scientists really did approach the problem in a novel, practical way, but their enemy is less wily than most adult cancers.)