The Story of Gleevec
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The Story of Gleevec
The drug imatinib mesylate (Gleevec®) was one of the early success stories in the search for targeted therapies. Its origins date back half a century, to the work of a scientist sometimes referred to as “the matriarch of modern cancer genetics,” Dr. Janet Rowley, who currently works at the University of Chicago Comprehensive Cancer Center.
In the 1960s, after a year in England as an NIH trainee, Rowley returned to Chicago and continued her study of the replication of DNA within normal and abnormal human chromosomes. She observed abnormal chromosomes in tissue samples from leukemia patients, but her work was impeded by the fact that the technology had not yet been developed to differentiate one chromosome from another.
On a subsequent trip to England in the 1970s, Rowley learned a new technique called chromosome banding, i.e., the use of special dyes to make adjacent segments of chromosomes distinguishable from one another by appearing darker or brighter when viewed under a microscope. Using this technique, chromosomes can be visualized as a continuous series of bright and dark bands, and each human chromosome pair has a unique banding pattern, somewhat like a bar code.
Returning to Chicago, Rowley identified a group of patients with acute myeloid leukemia (AML) whose chromosomes 8 and 21 had exchanged ends—the first known observation of what is now known as a chromosomal translocation. Looking at another group of patients, this time people with chronic myelogenous leukemia (CML), she found that chromosome 9 and another chromosome had also exchanged ends—another translocation. Subsequently, she found a third example when looking at patients with acute promyelocytic leukemia (APL), a rare form of leukemia. Rowley had discovered that translocated chromosomes play a role in leukemia, a finding consistent with the idea that cancer was a genetic disease.
Zeroing in on Leukemia
This thread was picked up in 1990 by a young oncologist, Dr. Brian Druker, who was working at the Dana-Farber Cancer Institute, part of the Dana-Farber/Harvard Cancer Center. Druker was treating patients with CML and was frustrated by his inability to stop the progression of the disease. Because he was aware of the genetic theory of cancer, he thought it should be possible to identify the genetic alterations that drive the growth of particular cancers and to develop safe and effective treatments that target those abnormalities.
Supported by an NCI career development award from 1990 to 1995, Druker began to work—first at the Dana-Farber/Harvard Cancer Center and later at the Oregon Health and Science University Knight Cancer Institute, both NCI-designated cancer centers—on a targeted therapy for CML. By the late 1990s, Druker’s scientific collaborators included Dr. Nicholas Lydon, a British biochemist, and Dr. Charles Sawyers of the Memorial Sloan-Kettering Cancer Center, who had begun this work while at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles.
Their new treatment targeted an abnormal cellular protein that is present in nearly all patients with CML. This protein, which is produced as a result of a genetic translocation involving chromosomes 9 and 22, is a hybrid, or fusion, protein called Bcr-Abl. The Abl portion of the fusion protein is much more active than the normal Abl protein, and this hyperactivity is the primary factor leading to CML. The investigators identified a specific compound as the basis for their new treatment, and then tested and modified it to enhance its ability to bind to Abl. The resulting drug, called imatinib (Gleevec®), killed CML cells by blocking the activity of Bcr-Abl protein. It was among the earliest targeted therapies that directly inhibit the activity of a cancer-causing protein.
First Clinical Trial on Imatinib
Imatinib was developed with drug company support, and the process moved very quickly. In June 1998, the first clinical trial of imatinib was launched at Oregon Health and Science University. Sawyers, from Memorial Sloan-Kettering, worked with Druker to design the first trial, including identifying the patients who were most likely to benefit from the drug. Subsequent trials were held around the country, and included other NCI-designated cancer centers.
In December 1999, Druker and his collaborators reported preliminary results from the first trial, finding that all 31 patients’ blood counts had returned to normal. In nine of 20 patients who were treated for 5 months or longer, no leukemia cells could be found. The side effects were minimal, and Food and Drug Administration (FDA) approval for the use of imatinib as a first-line treatment for CML came in record time, in 2001.
Imatinib was soon tested against other cancers, and, by 2011, the FDA had approved it for the treatment of several, including gastrointestinal stromal tumors.