(3 of 7)
Four years ago, for example, researchers at IDEC Pharmaceuticals in San Diego, Calif., hit just such a line-drive single with Rituxan, the first drug that successfully targeted proteins on cancer cells. Scientists had learned over the years that cancer cells are studded with an unusually large number of receptacles that compounds essential for survival, including growth factors, can plug into and fuel the cells' growth. Rituxan is a monoclonal antibody, a molecule specifically engineered to fit into the receptacles on non-Hodgkin's lymphoma cells and, in this case, single out the cancer cell for destruction by the immune system. Back in the early 1980s, monoclonal antibodies were hyped in the media as "magic bullets" that would wipe out cancer.
That proved far too strong a claim, but monoclonal antibodies have finally begun to live up to more modest expectations. Rituxan was the first, but just a year later, the same approach led to Herceptin, a drug that keeps growth factors from feeding certain kinds of breast-cancer cells. Such targeted treatments are effective only when the appropriate target exists. Herceptin, for example, latches onto a receptor known as HER2, which is abnormally abundant in only about 30% of breast-cancer tumors. A biopsy can tell doctors whether a patient is likely to respond to Herceptin, but they'd hoped to find a molecule that would plug into a growth-factor receptor more prevalent in cancer cells.
Sure enough, they found one. Dr. John Mendelsohn, then at the University of California, San Diego, and now president of the M.D. Anderson Cancer Center in Houston, had been focusing since 1981 on a receptor called EGFR, which is host to a protein called epidermal growth factor (EGF). It's a close cousin to HER2, and Mendelsohn and his team know that it is present in a huge variety of tumors; two-thirds of all cancer types, in fact, are blanketed with EGF receptors. In 1984 Mendelsohn and his team showed in mice that blocking the EGF receptor with a growth-factor decoy prevented a cell from growing and dividing.
Making a drug out of that decoy would prove tricky, since the receptor, like HER2, also shows up on noncancerous cells. Researchers are now learning, however, that normal cells are more adept than cancer cells at finding other growth factors on which to rely when EGFR is blocked. But when Mendelsohn applied for his first grant from the National Cancer Institute in 1983, he was rejected. "Nobody thought it would work," he says. The following year he turned to philanthropic sources for research dollars. Last year he wowed colleagues with a compound called IMC-C225, which proved effective in treating colon tumors in a small number of patients.
Then just this year researchers at Sloan-Kettering showed that the drug could dramatically boost the effectiveness of standard colorectal-cancer chemotherapy, shrinking tumors in more than a fifth of otherwise hopeless cases. Says Sloan-Kettering's Saltz: "The fact that we got a 20% response rate is staggering." What is happening, he surmises, is that the growth-factor inhibitor weakens the tumor enough for chemotherapy to finish it off.
Buoyed by those results, Saltz will begin testing IMC-C225 in less advanced patients this summer. And because combination therapy seemed to work so well, he is combining the EGFR inhibitor with not one but two chemotherapy agents to pack a triple punch.