Merging paths
In addition to being an exhilarating scientific chase, the discovery of the mutation at DFCI exemplified "bedside-to-bench" research: in other words, clinicians' observations about Iressa while treating patients led to insights in the laboratory. It's the reverse of the "bench-to-bedside" path, when basic laboratory science generates a therapy that improves care.
With support from the Barr Program at Dana-Farber, Matthew Meyerson, MD, PhD, (left) and William Sellers, MD, launched a search for abnormal proteins and discovered the EGFR mutation that makes the drug Iressa so effective against lung cancer.
In this case, crucial leads did come from the clinic. "The patients taught us about the biology of the disease through the pattern of their response to Iressa," says Pasi Jänne, MD, PhD, a Dana-Farber oncologist who used the drug in treatment and is a co-first author on the Science report.
As physicians gained experience with the new medication, a profile of likely Iressa responders began to take shape: nonsmoking women with NSCLC whose tumors were adenocarcinomas (affecting the lining of the lungs and secreting like glands). There was also an ethnic factor, as Japanese patients who fit this profile had a three-times-higher response rate than their counterparts in the United States.
Meyerson says he heard about this pattern at a scientific meeting in 2001, and that his first thought was a mutation, though not necessarily in EGFR.
The same year, Meyerson and Sellers launched a program, known as the Kinase Project, based on a brainstorm they shared on a plane. The idea was to scan the DNA sequence, or biochemical message, of the genes for all the known kinases in cancer cells, since faulty cell-growth switches have been found in several cancers. The scientists—working both at Dana-Farber and the Whitehead Institute/MIT Center for Genome Research in Cambridge, Mass.—would hunt for mutations in kinases, then try to match them up with kinase inhibitors that drug companies had previously developed.
In 2003, the kinase search was well afoot. Meyerson and Sellers focused their initial DNA sequencing efforts on lung and prostate cancer samples and specimens from leukemia patients. Among them were lung cancer specimens sent by Hidefumi Sasaki, MD, a surgeon at Nagoya City University in Japan and a former postdoctoral fellow at Dana-Farber.
By June of that year, the Kinase Project team was noticing EGFR kinase mutations in some of the lung cancer samples; they labeled the most common one L858R. In October, when the mutation findings were validated, Meyerson and Sellers immediately suspected a mutant EGFR-Iressa connection. They conferred by phone with Sasaki, who revealed that the samples containing L858R had come from nonsmoking Japanese women with lung adenocarcinomas. These women, however, had not received Iressa, so there was no information about drug response.
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