Hitting the bull’s-eye  pg. 3

“Suddenly we have two highly effective therapies for CML,” Rothenberg says. “This is like the grand slam home run.”

But CML appears to be a simple cancer, primarily driven by one genetic mutation, he adds.

“What we’re coming to realize is that the majority of cancers, especially solid tumors, tend to be polygenetic in origin,” he says. “It’s more than just a single dysregulated pathway, and so blocking a single pathway isn’t really sufficient in the majority of cases to cause true tumor regression.”

Signature response

It’s clear that the more specific a targeted therapy is—in terms of its target—the more restricted the patient population is that benefits from that drug, Carbone says.

“The reality is that lung cancer is probably 10, 15, 20 different diseases, driven by different molecular mechanisms and combinations that we’re just beginning to understand,” he says. “If we could find what subpopulations of tumors are driven by particular pathways, then we could find drugs to target those pathways and they’d be very effective in that subpopulation.”

Carbone’s laboratory was the first to identify a mutation in the epidermal growth factor receptor (EGFR) that predicts which lung tumors will respond to drugs such as gefitinib (Iressa) and erlotinib (Tarceva). In a manner similar to Gleevec, these drugs bind to and inhibit the receptor’s abnormal tyrosine kinase domain.

“We noted very early on at Vanderbilt that some lung cancer patients had a great response, but most patients didn’t,” Carbone says. The EGFR mutation that his group found in a patient’s tumor is found in about 10 percent of the U.S. patient population, and is “probably the best predictor of clinical response to these drugs.”

But the single mutation identifies only the “fantastic responders,” Carbone says. “Most studies are showing that there’s a much bigger set of lung cancer patients who will benefit from these drugs.”

Through the National Cancer Institute’s Strategic Partnering to Evaluate Cancer Signatures (SPECS) program, Carbone and his colleagues are searching for the “molecular signatures” that will predict which lung cancer patients will benefit from Tarceva.

They have found eight proteins in the blood that together “really seem to identify patients who will live longer when they are treated with erlotinib,” Carbone says. He presented the findings last June at the American Society of Clinical Oncology meeting in Atlanta.

These kinds of molecular signatures or “profiles” will be key to successfully using targeted therapies and moving them to earlier stages of treatment.

Clinical trials of new drugs start in the sickest patients—those with metastatic disease for which there is no known effective therapy. These patients have already endured the standard therapies, and the probability of anything working at that point is probably remote, Johnson says.

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