Gleevec: the Breakthrough in Cancer Treatment

The Gleevec story began in earnest in the late 1950s, when researcher Peter Nowell and graduate student David Hungerford were studying leukemias and lymphomas. As Nowell (2007) recounts:

I knew nothing about cytogenetics at this time but felt that the chromosomal preparations of the leukemic cells warranted investigation for any abnormalities . . . Hungerford and I, as well as other researchers around the world, began to use the new cytogenetic techniques to determine whether human leukemias could be characterized by specific chromosome abnormalities.

Of course, a great deal of cancer research had already occurred prior to Nowell and Hungerford's work, beginning in the late 1800s when scientists first speculated on "mitotic abnormalities" (i.e., chromosomal abnormalities) and their potential role in the formation of human tumors. Later, in 1914, biologist Theodor Boveri was among the first to articulate a series of hypotheses about the potential role of chromosomal abnormalities in tumor formation. These ideas were ignored by most of the scientific community for many years, mostly because researchers didn't have the tools to test them. Not until scientists had access to more sophisticated techniques, such as the use of colchicine in chromosome preparations (colchicine arrests the cell cycle in the middle of mitosis, at which time it is easiest to view and analyze chromosomes), were they even able to accurately count the number of human chromosomes. Indeed, during the 1950s, researchers continued to rely upon these techniques as they began finding connections between abnormal chromosome number and various human diseases, like an extra copy of chromosome 21 and Down syndrome. This was also the period during which Nowell and Hungerford would be among the first researchers to identify a connection between a chromosomal abnormality and cancer.

Nowell and Hungerford started their search by investigating cells from individuals with acute myelogenous leukemia (AML). They found no consistent chromosomal abnormalities in these patients. This trend continued until the duo began to work with patients with CML. At this time, Hungerford noticed an atypical small chromosome in cancer cells from two patients with this disease. Expanding their search, the scientists also found the same unusual small chromosome in five other CML patients. This chromosome was soon dubbed the "Philadelphia chromosome," named after the city in which it had been discovered. Thereafter, the finding that nearly all cancer cells from patients with CML carried the Philadelphia chromosome was strong evidence that the researchers were onto something significant.

Indeed, while later scientists would go on to discover that nearly all cancer cells have some kind of abnormal chromosome pattern, no other pattern displays the same consistency as CML does with the Philadelphia chromosome. Thus, scientists now believe that in many cancers other than CML, chromosomal abnormalities are a consequence rather than a cause of the disease.

Figure 1: The Philadelphia chromosome

Discovered in 1960, the diagnostic karyotypic abnormality for chronic myelogenous leukemia is shown in this picture of the banded chromosomes 9 and 22. Shown is the result of the reciprocal translocation of 22q to the lower arm of 9 and 9q (c-abl to a specific breakpoint cluster region [bcr] of chromosome 22 indicated by the arrows).

© 2006 Peter C. Nowell Courtesy of Peter C. Nowell, MD, Department of Pathology and Laboratory in the Perelman School of Medicine at the University of Pennsylvania. All rights reserved.

In the decades following Nowell and Hungerford's discovery, cytogenetic techniques were refined even further. For example, scientists developed new ways to treat and dye chromosomes so that their organization and substructure were clearly visible when examined through a light microscope. This allowed researchers to be able to home in on the actual genetic event that gave rise to the Philadelphia chromosome.

Janet Rowley, a biologist at the University of Chicago, was among the first scientists to use some of these new techniques to study the Philadelphia chromosome. Rowley examined cells from nine CML patients and discovered that the Philadelphia chromosome looks the way it does because it is actually a translocated chromosome, or a fusion of parts from two different chromosomes (Rowley, 1973). Specifically, the Philadelphia chromosome is a variant of chromosome 22 that is missing its long arm and, instead, has the long arm of chromosome 9. The transfer between the long arms of chromosomes 9 and 22 is called a reciprocal translocation. In Figure 1, the arrows indicate the translocation breakpoints for each of the involved chromosomes. The smaller chromosome 22 on the right is the Philadelphia chromosome.

Following Rowley's work, it took another 10 years before scientists were able to determine the actual genes involved in the Philadelphia chromosome translocation. This milestone took place in 1983, when researchers from the National Cancer Institute and Erasmus University demonstrated that the human c-abl oncogene is located in the region of chromosome 9 that translocates to become part of the Philadelphia chromosome (Heisterkamp et al., 1983). Then, in 1984, the same group of researchers identified what they called the breakpoint cluster region (bcr), or the 5.8-kilobase region in which all the chromosome 22 breakpoints seemed to occur in CML patients with the Philadelphia chromosome (Groffen et al., 1984). The researchers thus concluded that these two genes, together known as the bcr-abl fusion, were likely the molecular culprits responsible for CML. Their suspicions were confirmed in 1990, when scientists from the Whitehead Institute in Cambridge, Massachusetts, infected bone marrow cells with a retrovirus encoding the fusion gene and demonstrated that, indeed, the presence of an active bcr-abl gene initiates CML or CML-like symptoms (Daley et al., 1990).

Also in 1990, researchers from the University of California, Los Angeles, identified the function of the bcr-abl fusion gene: production of an abnormal tyrosine kinase protein that is not properly regulated (Lugo et al., 1990). Tyrosine kinase is a common signaling molecule that, when activated, triggers cells to divide. In patients with CML, the mutated tyrosine kinase is active for far too long, causing cells to proliferate at an abnormally high rate. This proliferation results in the overproduction and accumulation of immature white blood cells, which is the hallmark of CML. In fact, whereas cubic millimeter of blood from a healthy person contains about 4,000 to 10,000 white blood cells, the same volume of blood from a person with CML contains 10 to 25 times that amount.

Thus, after 30 years of basic scientific research, the stage was finally set for the development of a drug that countered CML. The fact that this disease was caused by only a single aberrant protein meant that drug developers had just one easy-to-see target. Their next step was to figure out how to hit that target—in other words, to determine how to stop the aberrant tyrosine kinase molecules from driving uncontrolled cell growth.