We Fought Cancer…And Cancer Won.

Biologists who never met a signaling pathway they didn't love tend to dismiss the success in pediatric oncology. It involved no discoveries of elegant cell biology, just plodding work. Ironically, however, it is these "singles," not the grand slams of molecular biology, that have made the greatest difference in whether people develop cancer and die of it. Fewer smokers (54 percent of men smoked in 1971; 21 percent do today), more women having mammograms and fewer taking hormone-replacement therapy (the incidence of breast cancer fell an unheard-of 7 percent from 2002 to 2003, after a 2002 study found that HRT can stimulate the growth of tiny breast tumors) have had at least as great an impact on cancer as the achievements of basic-science labs that received the bulk of the funding in the war on cancer. Similarly, the widespread use of Pap smears to detect precancerous changes in cells of the cervix is almost entirely responsible for the drop in both incidence of and deaths from cervical cancer. Incidence has fallen some 65 percent since 1975, and mortality at least 60 percent. Little wonder, then, that by the 1980s critics were asking why the war on cancer was spending the vast majority of taxpayers' money on elegant biology that cured millions of mice rather than on the search for more practical advances like these.

By "critics," we don't mean disgruntled laypeople. At UCLA, Denny Slamon had been inspired by Robert Weinberg's discovery of the first human oncogene, ras, in 1982. Although drugs to squelch the gene directly did not pan out, the discovery did lead to the first real success of the reductionist, "let's get in there and study the genetics and molecules of cancer" approach. Slamon was at first following the crowd, examining animal cancers for signs of DNA changes. But in 1982 he had an idea: look for unusual genes in tissue samples taken from human tumors. He applied to NCI for funding and, he recalls, "they basically sent it back with a laugh track. They said it was just a fishing expedition, that it wasn't hypothesis-driven. We tried to explain the logic—that if cancer reflects a problem of genetic control, then finding mutated genes should be important—but still didn't get funded." The same year that NCI laughed at Slamon's idea, MIT's Weinberg and colleagues discovered another gene involved in cancer. Called HER2, it makes a molecule that sits on the outside of cells and acts like an antenna, picking up growth signals that are then carried to the cell nucleus, where they deliver a simple if insidious message: go forth and multiply, really really fast. That made Slamon wonder whether HER2 might play a role in major human cancers.

In 1984, backed by private funding, Slamon found that 27 percent of breast cancers contain extra copies of HER2. Over the next decade he and other scientists showed that HER2 caused the cancer, rather than being an innocent bystander (or "marker," as scientists say). They also found an antibody that attaches to HER2 like a squirrel's nest on a TV antenna, preventing it from picking up signals. In 1998 the FDA approved that antibody, called Herceptin, for use in breast cancers fueled by HER2. It was stunning proof of the principle that drugs could be precisely crafted to cripple molecules that lie upstream of cell replication, stoking the growth of cancer cells and only cancer cells, not healthy ones, and has cured thousands of women. After the 1984 discovery, NCI was happy to fund Slamon. "It was only because we had already shown that the research would work," he says wistfully. "It is, shall we say, a conservative way to spend your money."

Slamon was not the only scientist who noticed NCI's preference for elegant molecular studies over research that offered the possibility of new treatments. (We should note that funding decisions are made not by NCI bureaucrats but by panels of scientists from, mostly, universities and medical institutions.) In the mid-1990s Brain Druker of the Oregon Health and Science University Cancer Institute wanted to study a molecule involved in chronic myelogenous leukemia. Targeting that molecule, he thought, might cure CML. "People rolled their eyes and asked, 'What's new and different about this?' " By "new and different," they meant scientifically novel, elegant, offering new insight into a basic cellular process. He didn't even apply for an NCI grant. "I knew I'd just be wasting my time," he says. "NCI would have looked at what I wanted to do and said it was too high-risk. Instead I took the tried-and-true approach of getting funded for basic research, seeing how cell growth is regulated" by molecules that are grabbed by receptors on a leukemia cell and that send proliferation orders to the cell nucleus. This work led to a useful clinical test, but the work NCI did not fund (a private foundation did) eventually led to Gleevec, the blockbuster CML drug.

Indeed, there is no more common refrain among critics of how the war on cancer has been waged: that innovative ideas, ideas that might be grand slams but carry the risk of striking out, are rejected by NCI in favor of projects that promise singles. "We ask the scientists all the time why aren't we further along," says Visco. "Part of the answer is that the infrastructure of cancer is to keep things moving along as they have been and to reward people doing safe research. Exciting new ideas haven't fared well." As coincidence would have it, in the very year that Nixon launched the war on cancer, an unknown biologist named Judah Folkman published a paper proposing that metastatic cells survive, and become deadly, only if they grow blood vessels to keep themselves supplied with nutrients. That process is called angiogenesis, and it had nothing to do with the genes and proteins that the soldiers in the war on cancer were fixated on. Throughout the 1970s "the reaction was mainly hostility and ridicule," Folkman (who died earlier this year) recalled to NEWSWEEK in 1998. "People would ask me [at scientific meetings], 'You really don't believe that, do you?' " NCI turned down his request for funds to continue his work, calling his ideas about the importance of angiogenesis in metastasis "just your imagination," Folkman said. He persisted, of course, laying the groundwork for what would become anti angiogenesis drugs. Avastin was approved for colorectal cancer in 2004.

If the 1990s were the era of identifying cellular processes and molecules unique to cancer cells—not the blunderbuss approach of wrecking DNA and stopping replication, which brings friendly fire down on healthy cells—the focus of the 2000s is to personalize treatment. The reason is that, just as cancer cells develop resistance to standard chemo drugs, so they are finding ways to elude the new targeted drugs such as Avastin, Gleevec and Herceptin. In the studies that led the FDA to approve Avastin, for instance, the drug prolonged life in patients with advanced colorectal cancer by a median of four months. In later studies, it increased survival in advanced lung-cancer patients by a couple of months, says Roy Herbst, a lung oncologist at M. D. Anderson. Why so little? "Angiogenesis is a redundant process," Herbst explains. "Most cells use the VEGF pathway [that Avastin blocks], but there are at least 12 other pathways, and Avastin doesn't block any of them." With VEGF out of commission, malignant cells turn to these alternatives. Or consider Tarceva, given to lung-cancer patients, which turns off a molecule called EGFR that fuels the proliferation of some lung and other cancer cells. "It shrinks the tumor 60 to 80 percent of the time, and the effect lasts about a year," says David Johnson, a thoracic oncologist at Vanderbilt (University) Ingram Cancer Center. But if even a tiny fraction of malignant cells in the tumor or at metastatic sites use a proliferation pathway other than EGFR, they laugh off Tarceva and proliferate unchecked; most patients are dead within three years. Of the first patients with a rare gastric cancer whom George Demetri of Dana-Farber treated with Gleevec in 2000, 85 percent became resistant to it after five years. (Before Gleevec, though, patients with this cancer died within six weeks.) The malignant cells, it turns out, change the shape of the molecule that Gleevec blocks. It's as if a teenager, knowing Mom has a key to his room and wanting his privacy, changed the lock before she arrived.