Closing In on Cancer

The idea that a cure for cancer might be just around the corner got a lot of attention a few years ago after James Watson, co-discoverer of the structure of DNA, was quoted on the front page of the New York Times saying that it was going to happen within two years. Watson later claimed he had been misquoted; he had meant to predict only that certain compounds designed to starve cancerous tumors would be proved effective in two years.

Well, it's been three years, and cancer is clearly still with us. But dramatic progress has been made. Last week the U.S. Food and Drug Administration announced with great fanfare the approval of a new drug, Gleevec, that doesn't cure all cancers but seems to be effective in treating two rare types that are particularly resistant to conventional treatment (see story below). Meanwhile, the broader approach Watson was promoting--one that would work against a wide array of cancers--is still very much alive and may yet deliver on its original promise.

The promise was this: by cutting off the blood supply of a tumor, you can kill it before it spreads. This is called antiangiogenesis (the prevention of new blood-vessel growth). The concept, first championed by Dr. Judah Folkman of Children's Hospital in Boston, launched thousands of research studies. But the concept of antiangiogenesis hasn't gone well lately. Major pharmaceutical firms have stopped work on their favorite antiangiogenesis candidates, and not one of the 50 other compounds under study has yet been approved by the FDA--despite three decades of research and an investment of some $4 billion.

What happened? Last week, just before the annual meeting of the American Society of Clinical Oncology, a panel made up of some of the leading researchers in the field gathered in San Francisco to address that question. The fault, they concluded, is not in the new anticancer compounds--in which the researchers still have great faith--but in the way they are being evaluated. "We've gone past the first hurdle, where we wondered whether they would ever work in anything other than a mouse," says Dr. Lawrence Einhorn, president of asco. "The challenge now is how do you study them?"

Traditional chemotherapy compounds are like blunderbusses that kill both malignant and healthy cells indiscriminately--by bombarding tumors with as much cell-destroying chemical as the patient can handle. Angiogenesis inhibitors, by contrast, are smart missiles. Like Gleevec, they belong to a new breed of cancer-fighting agents that grow out of a deep understanding--at the molecular level--of how cancers grow, and are designed to block a particular step along the way.

Unfortunately, current drug trials, even for new cancer treatments, are based on the old chemotherapy model. Success is measured by how much tumors shrink--or disappear--within a few days or weeks. Because angiogenesis inhibitors work on the blood vessels that feed tumors rather than on the tumors themselves, they usually take longer, sometimes as much as a few months, to show any effect.

So Step 1, the scientific panel concluded, was to change current trial design to give the new drugs more time to work. As a second step, the panel also wants to change the criteria by which a drug's success is measured. The group proposed that with the newer, better-targeted medications, success should be determined not by whether a tumor shrinks in size but by whether it can be confined, or by how long a patient can put off chemotherapy.

In the next few months, these recommendations will be compiled by the Angiogenesis Foundation, a nonprofit clearinghouse for research in the field, and forwarded to the FDA and the National Institutes of Health, which funds the bulk of cancer research.

Meanwhile, some of the latest angiogenesis studies have already incorporated lessons learned in the early trials. Initially, most blood-vessel inhibitors were tested alone as potential magic-bullet treatments, and in patients with advanced cancer. But scientists now have a better understanding of how angiogenesis inhibitors prevent growth factors from reaching blood-vessel cells. They believe that, for now, in terminally ill patients, the best you can expect of the experimental drugs is to keep tumors from spreading. So researchers have begun to evaluate them in conjunction with traditional chemotherapy, radiation and surgery. So far, the results are promising. Preliminary trials involving patients with advanced non-small-cell lung cancer and kidney cancer suggest that the combination of angiogenesis inhibitors with standard therapy improves survival rates beyond those of either treatment alone.

Ultimately, if cancer treatment shifts to include the new drugs, the definition of cancer may have to evolve. "Someday," says Folkman, "we may treat cancer as a chronic, manageable disease, very much like we treat heart disease now." Until then, the trials continue.