JANUARY 22, 2001 VOL. 157 NO. 3

The Hunt for Cures

Cancer
Smart bombs for targeting deadly tumors
By SHANNON BROWNLEE

ALSO
The Future of Drugs
Now that our DNA has been decoded, the search for better, faster and more effective medications begins in earnest
• Inside the Brave New Pharmacy: At a leading genomics firm, the star of the show is a robot
• DNA Microarrays: The workhorse of genomic medicine
• Bioinformatics: How to design a molecule
• The Search for Cures: The fight against aids, cancer, mental illness, obesity, Alzheimer's

Frank Mccormick was flying home from a meeting on cancer genetics when a wild idea popped into his head. What if you could make a virus that would infect—and kill—cancer cells but leave healthy cells intact? The next day, McCormick excitedly explained his notion to colleagues at Onyx Pharmaceuticals in Richmond, U.S., a biotech company he had founded earlier that year. Some of them were as enthusiastic as he was. Others told him he was crazy; such a treatment couldn't possibly work.

Nine years later, McCormick, now director of the Comprehensive Cancer Center at the University of California, San Francisco, has proof of his sanity in the form of Onyx-015, a virus that works exactly as he envisioned. Last year the company reported results of a clinical trial in which Onyx-015 injections, in combination with chemotherapy, melted away tumors in 8 out of 30 patients with recurrent, late-stage head and neck cancer. In another study, involving 27 patients whose cancer had metastasized to the liver (a condition that usually kills in 6 months), 11 were still alive nearly two years after being treated with high doses of Onyx-015.

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McCormick's story is one of hundreds of similar tales coming out of laboratories and cancer wards around the world, as treatments that were little more than half-baked ideas a decade ago now enter the final stages of testing. Of some 350 new compounds and molecules being tested on cancer patients, more than half are based on innovative, sometimes bizarre-sounding ways of homing in on tumors. Hundreds more are in earlier stages of development, putting clinicians and drug companies in the novel position of having more promising cancer treatments waiting to be evaluated than they can possibly handle.

The new therapies are emerging from two extraordinary decades of intense basic research, a fantastic voyage that scientists have taken into the heart of the cancer cell. "The life and death of cells is being worked out, and the dozens and dozens of molecules in the body that participate in those pathways are now becoming targets for therapy," says Alan Houghton, a medical oncologist and immunologist at Memorial Sloan-Kettering Cancer Center in New York City.

That's welcome news to clinicians and patients alike. Traditional cancer treatments—chemotherapy and radiation—are therapeutic blunderbusses; they blast indiscriminately at all fast-growing cells, often destroying healthy tissue along with the tumors. By comparison, the new drugs are smart bombs; they cause minimal collateral damage and trigger relatively few side effects.

Many of the new therapies also happen to be incredibly potent. Last month, for example, pharmaceutical giant Novartis reported spectacular results in a clinical trial of Glivec, a drug that disables a uniquely aberrant protein produced inside cells of chronic myelogenous leukemia. In the drug's very first test, every patient went into remission. In the most recent results, 30% showed no sign of the chromosomal damage that marks the disease and appeared to have been cured. "This drug is amazing," says Richard Stone, an oncologist at the Dana-Farber Cancer Institute who has been testing Glivec (also known as an STI, for signal transduction inhibitor). "Even patients who are near death, at the end stage of this disease, are going into remission."

Glivec is just one of several new therapies that work by cutting a cancer cell's lines of communication, either preventing it from reproducing or forcing it to self-destruct. Other signal-jamming treatments use monoclonal antibodies, tiny proteins that resemble the human immune system's own antibodies but that bind to the surface of cancer cells. New York City- based ImClone Systems has an antibody called IMC-c225, now in the final phases of testing in colorectal and head and neck cancer, that acts like bubble gum stuffed in a keyhole. It prevents a specialized protein known as a growth factor from fitting into a slot on the surface of the cancer cell and signaling it to reproduce.

Other antibodies carry tiny payloads of radioactive isotopes or poisons, which kill the tumor cell without affecting surrounding tissue. IDEC Pharmaceuticals in San Diego, U.S., has just completed final rounds of testing on Zevalin, an antibody that is hooked to the radioactive isotope yttrium-90. Last month IDEC reported that the tumors in about one-third of 73 late-stage non-Hodgkins lymphoma patients were undetectable after being treated with Zevalin.

Antibodies are also being drafted to prod the immune system into attacking cancer cells. Clinicians have long dreamed of marshaling the body's own defenses to fight cancer, if only they could get the immune system to recognize cancer cells as easily as it spots foreign invaders such as bacteria and viruses. Researchers at Dendreon Corp. in Seattle have found a way to do just that by enlisting dendritic cells, some of the body's most potent immune stimulators.

Two years ago, Mohammad Omidian, 58, a general contractor from Orinda, U.S., had failed to respond to chemotherapy treatments for multiple myeloma that was eating away at his bones. He had shrunk 8 cm and was so weak, he says, "I could not sneeze without holding on to something." His doctors put him on Dendreon's experimental treatment Mylovenge, which required extracting dendritic cells from Omidian's blood, mixing them with molecules from myeloma cells and then returning them to the patient so they could deliver a swift kick to his immune system. Within two weeks, Omidian felt strong enough to return to work. Within two months, his cancer was in a remission that lasted until late last year, when he resumed treatment with Mylovenge.

Other companies are focused on boosting the immune system with vaccines that can direct it to target cancer cells. A new vaccine developed at Memorial Sloan-Kettering binds a protein from a mollusk called a limpet to seven different types of sugars and a protein fragment found only on cancer cells. The vaccine is then mixed with saponin, a soaplike derivative from a South American tree. This witch's brew serves to annoy the immune system, revving it up enough to attack cancer cells that are carrying the same sugars and protein fragment.

Such therapies will not, on their own, be able to rid the body of large tumors. So it is likely that oncologists will put together cocktails of treatments, each using a different strategy to outfox the cancer. In the future, traditional chemotherapy will be combined with other cell-killing treatments like the cox-2 inhibitors, drugs that are chemically related to pain-killers like ibuprofen and that appear to force cancer cells to self-destruct. Chemotherapy will also be used with treatments that aim simply to stop tumors from growing, such as the so-called antiangiogenic factors, relatively nontoxic compounds that blunt the growth of new capillaries.

Tumors, it turns out, cannot grow much beyond the size of a peppercorn without an ever expanding network of blood vessels. Clinicians are testing more than a dozen treatments aimed at halting that process, including some old-line drugs that have turned out to have antiangiogenic properties. Thalidomide, which caused devastating birth defects in some 12,000 children worldwide before it was withdrawn in the early 1960s, is finding a new lease on life against multiple myeloma and liver cancers. Pharmaceutical giant Bristol-Myers Squibb is testing an antiangiogenic drug that was initially developed to keep cancer from worming its way into surrounding tissue. It's also investigating whether low, steady doses of traditional chemotherapy may be able to beat back blood vessels, a treatment that would have the added benefit of minimal side effects.

It's clearly too soon to declare victory in the war on cancer, since 9 out of 10 new treatments will fail clinical trials. But doctors who treat the disease are experiencing a surge of optimism the likes of which they have never felt before. "It's no longer spin the wheel, let's try this drug, maybe it will work," says Henry Friedman, a neuro-oncologist at Duke University Medical Center. "We're going to know why a drug is or isn't working." And given the nature of cancer and the scientists who study it, if one approach doesn't fly, there will be no shortage of other ideas to try.

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