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Another reason cancers grow inexorably is that unlike normal cells, which die a natural death after a fixed number of divisions, cancer cells live forever. Scientists have been looking for compounds that will rewire tumor cells so they will know when it's time to go. The research is still in its early stages, but scientists in several labs have started looking at a group of enzymes called caspaces; inhibiting these enzymes disrupts the process of DNA repair that occurs each time a cell divides.
In Cambridge, Mass., Millennium Pharmaceuticals is focusing on proteins called proteasomes, which evidently play a role in giving cancer cells unnaturally long lives. The company is in Phase II trials with LDP341, a proteasome-inhibiting substance that is showing promise against multiple myeloma and chronic lymphocytic leukemia. Phase I studies on the top five solid tumors (breast, pancreatic, prostate, lung and colon) are under way, and at this point the inhibitor seems to be working - at least in mice.
By far the most celebrated of the new cancer fighters are the antiangiogenesis drugs. Like monoclonal antibodies before them, these compounds, which keep tumors from growing their own blood supplies, were briefly touted as magic one-shot cancer cures - although Folkman, who pioneered the field in the 1970s, was always circumspect about making premature claims. "I think the antiangiogenesis field got some unfair negative publicity," says Saltz. "Our expectations were too high, but there is a lot of brilliant science behind it."
Indeed, while the execution has proved difficult, the idea is very simple. Tumors, like any other cells, need oxygen and nutrients to survive. At first they eat their way through healthy tissue, looking for blood vessels to tap for these essentials. Eventually, though, they start to grow their own capillaries and vessels, like oil companies eager to guarantee a steady flow of crude.
Folkman's insight was to look for substances that prevent tumors from building those pipelines. This approach worked beautifully in mice. Now more than 50 angiogenesis inhibitors are being studied in humans with a wide range of cancers; a dozen are in the final stages of testing. Thus far, only a tiny number of human patients treated with these compounds have seen their tumors shrink or disappear. Clinicians are nonetheless encouraged; while angiogenesis inhibitors don't make cancer go away, they do appear to slow tumor growth. And that means they may work best in conjunction with some of the other new treatments to batter cancer from several directions at once.
"We've seen results in very few patients yet," says Folkman. "But we have seem some patients with stable disease. We have seen some patients whose tumors have stopped growing. And we have seen some patients whose tumors slowly regressed. I think the approach is promising, but we are still learning."
While many scientists focus their attention on potential weaknesses in the cancer cell, others are concentrating on the flip side - recruiting the body's immune system to seek and destroy the renegade tissues. So far, this approach has proved less successful, largely because no matter how badly they are misbehaving, tumor cells are purely homegrown and thus presumed innocent by the immune system. When it finally catches on that something is wrong, it's usually too late.
That problem may not be insurmountable, as scientists at last week's clinical-oncology meeting made clear. The trick, it turns out, may be to put aside 99% of the immune system and focus on dendritic cells, a tiny but especially sensitive population of white blood cells that act as sentries to warn against invaders of all kinds. Scientists at California-based Cell Genesys, for example, have taken tumor cells from a number of cancers, genetically engineered them to pump out a hormone that stimulates production of a host of immune cells, and vaccinated late-stage lung-cancer patients with the mixture to boost chances that dendritic cells would sound the alarm against the tumors. In the latest study, three of 22 patients saw their tumors disappear completely, and four saw them stop growing.
Researchers at Stanford University have harvested dendritic cells from advanced-cancer patients, exposed the cells to potent growth factors, added tumor-specific proteins to sensitize them and reintroduced the mixture into patients as a vaccine. Of 12 patients with advanced colorectal and lung cancer, two watched their tumors shrivel away, and another is still tumor free a year after receiving the vaccine.
Whether you're talking about conventional therapy or one of these promising new approaches, experts agree the earlier you catch a cancer, the better your chances of controlling it. And thanks to a growing understanding of the cancer cell's natural life cycle, doctors are learning how to detect the disease at its very earliest stages. One well-known example is the prostate-specific antigen (PSA) test, which identifies a protein secreted by abnormally growing prostate cells before any symptoms appear. (The test is not perfect, however, since PSA is also secreted, albeit in smaller amounts, by benignly growing prostate cells.)
Researchers such as Dr. David Sidransky, an oncologist at Johns Hopkins University, are searching for diagnostics that will pick up other cancers in their preliminary stages. Others are focusing on an even earlier stage, trying to lower the risk of developing cancer to begin with. Here the most exciting work centers on the cycooxygenase inhibitor called COX-2. This pain reliever was originally developed to clamp down on inflammation as aspirin does but without aspirin's tendency to eat through the lining of the stomach.
It turns out that COX-2 inhibitor drugs also have anticancer effects, reducing the number of precancerous polyps in patients with a hereditary form of colon cancer, perhaps through antiangiogenesis. Scientists are currently studying its effect on noninherited colon cancers. And because the receptor for COX-2 is overexpressed on a range of human cancer types, the hope is that COX-2 inhibitors may be useful in preventing a wider range of cancers, including head and neck, bladder, nonsmall cell lung and breast cancers.
As promising as these therapies are, there remain many questions for researchers to answer. Among the most important: Which treatments should be given to which patients? Says Sidransky: "Within five years, it might be almost impossible to bring a drug forward without having a test to help doctors decide whom the drug is for."
Eventually, the goal is to detect precisely which molecular processes have gone wrong in an individual patient's cancer. Rather than being identified as lung cancer or breast cancer or kidney cancer, tumors will be tagged as EGFR positive, for example, or COX-2 positive. "The dream," says M.D. Anderson's Mendelsohn, "is that if Mrs. Smith gets a breast biopsy, we'll be able to say, 'Here are the four genes that are abnormal in her tumor,' pull open a drawer, pick out the antibodies or small molecules designed against the abnormal products of those genes, and give her a cocktail targeting the genes that caused her cancer."
That dream comes at a price. Staying on Gleevec, for example, may end up costing patients like Victoria Reiter as much as $2,400 every month - nearly $30,000 a year - for the rest of her newly prolonged life. While the National Cancer Institute funds basic research into cancer biology, the bulk of drug development is done by for-profit pharmaceutical firms. These companies claim that it costs them between $500 million and $1 billion to bring a single new medicine to market - partly because it can take 15 years for the exhaustive testing in animals and humans required by U.S. law and partly because for every medicine finally approved by the FDA, 5,000 others fail somewhere along the way. The drug companies count on that one success to pay for the 5,000 failures. Meanwhile, pharmaceutical firms are under attack both for allegedly conspiring to keep cut-rate competitors out of the market and for profiting handsomely from basic research that was originally funded by the taxpayers.
Now that Gleevec has been taken off the experimental list, insurance companies will probably pick up the tab. Cancer most often strikes the elderly, however, and Medicare's role in paying for prescription drugs is still undecided. President Bush's drug plan would add $153 billion for Medicare drug benefits through 2011. Democrats call the amount "inadequate," and even congressional Republicans agree it is not enough. The final numbers will be hammered out later this year.
At least the drug companies and politicians have something to argue about. Given the painfully slow development of effective cancer treatments over the past three decades, the flood of positive results reported at last week's oncology conference was especially gratifying. "Cancer treatment has always been a satisfying profession," says Dr. Michael Gordon, a cancer specialist at the University of Arizona. "But now it's truly exciting. I've been wondering to myself about where I will be in 20 to 25 years, and I'm thinking that I might just be out of a job. And that will be great."
With reporting by Dan Cray/Los Angeles and Christine Gorman/New York