A Step Past Chemotherapy

Cancer researchers are a stubborn lot. They know the numbers: more than 16,000 people die from cancer every day. They know the enemy: an insidious disease that ravages virtually every organ in the body. And they know that they desperately need new treatments so that patients like Amelia Gilardi, 72, become the norm, not the exception. In 1998, Gilardi was diagnosed with multiple myeloma and told she had no more than three years to live. After traditional chemotherapy failed, Gilardi enrolled in a clinical trial of a then experimental drug called Velcade. Eight months later she was in remission. "It was wonderful that there was something else out there," she says.

For decades, doctors have relied on conventional chemotherapy to poison cancer cells. The treatment has saved many lives, but because chemo attacks healthy cells, too, patients suffer a slew of toxic side effects. And they often become resistant to treatment or die from complications. Today, thanks to an increasingly sophisticated understanding of how cancer works, patients are beginning to benefit from a revolution in oncology: targeted drugs that home in on the molecular characteristics of cancer cells, leaving healthy tissue relatively unscathed. There are still no miracle cures, but there is plenty of cautious enthusiasm. "These are small incremental gains," says Dr. David H. Johnson of the Vanderbilt-Ingram Cancer Center, "but each one is phenomenal."

Cancer was long thought of as one disease expressed in different parts of the body, but researchers are now teasing apart the myriad genes and proteins that differentiate cancer cells, not just from healthy cells, but from each other. Two breast-cancer tumors may look identical under the microscope, but may turn on, or "express," different genes. The result: two tumors behaving in dissimilar ways--and susceptible to different treatments.

Targeted drugs go after these different genes and proteins, interrupting various pathways in the vast molecular network that keeps cancer alive. One significant advance in this new approach is Gleevec, approved in 2001 to treat chronic myeloid leukemia. Gleevec clamps down on the cell's accelerator, a protein called tyrosine kinase, which drives cancer to reproduce. Now other tyrosine kinase inhibitors are making their way to market. In trials, Iressa has shown a modest benefit to patients with lung cancer who had failed prior chemo. The drug may ultimately work best as a maintenance therapy in combination with other drugs, to keep tumors suppressed.

Targeting the cell's growth machinery has long been the goal of antiangiogenesis, which attempts to cut off a tumor's blood supply. Now scientists have a target: vascular endothelial growth factor, a protein that recruits blood vessels to feed tumors. Today the first angiogenesis inhibitor, Avastin, is under review for metastatic colon cancer.

Velcade, Gilardi's drug, was engineered to zero in on the cell's garbage disposal. The drug seems to work by stopping an enzyme, the proteasome, from degrading proteins no longer needed by the cell. By gumming up the disposal, Velcade leads the cell to biological suicide. Like other therapies, Velcade may turn out to work best as an adjunct treatment.

Targeted drugs can be expensive (in some cases, $20,000 or more). They still have side effects. And despite their design, researchers aren't always sure precisely how they work. The critical challenge now is to fine-tune the diagnosis and treatment of cancer, so that the right drug is matched to the appropriate patient. "If that happens," says Dr. Charles Sawyers of UCLA's Jonsson Comprehensive Cancer Center, "we're really going to see a lot of progress."

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