Imatinib mesylate (Gleevec) burst onto the clinical scene to much fanfare in 2001. One of the first targeted therapies to be used successfully against a cancerchronic myeloid leukemia (CML)imatinib has since proven effective in treating other diseases, such as gastrointestinal stromal tumors. Now, new research shows that imatinib is also effective against a rare blood disorder called hypereosinophilic syndrome (HES). Not only has the drug shown remarkable results in about 50% of patients with HES in whom it has been used, it has revealed a previously unknown mechanism that is responsible for some cases of HES.
Gary Gilliland, M.D., Ph.D., associate professor of medicine at Brigham and Womens Hospital, Boston, and colleagues recently published a study that revealed a genetic abnormality that was responsible for some cases of HES. Their results suggest that at least in a subset of patients, HES may be considered a form of cancerchronic eosinophilic leukemia.
The overproduction of eosinophils occurs in various conditions, including parasitic infections, autoimmune diseases, and asthma. However, in some cases there is no apparent cause for the rise in eosinophils, and the condition is diagnosed as idiopathic HES. Immunologist Gerald Gleich, M.D., of the University of Utah, Salt Lake City, pointed out that HES is actually a collection of rare diseases that were lumped together under this rubric in the 1960s. Whatever the cause of HES, if unregulated eosinophilic growth is not checked, these white blood cells can accumulate in various organs throughout the body, causing damage and eventually death. Drugs such as interferon alpha, hydroxyurea, steroids, and cytotoxic chemotherapy have been used to treat HES. But patients do not always respond to these therapies, and even when they do, the side effects can be severe.
Understandably, patients and researchers have sought a less toxic and more effective treatment for this rare but deadly disease. As Gleich pointed out, although CML and HES are distinct diseases, they share certain clinical characteristics, and similar drugs are used to treat both disorders. So when imatinib yielded remarkable results in patients with CML, it raised the question of whether the drug could also be effective in HES.
Soon after the drug was approved for the treatment of CML, Gleich, then at the Mayo Clinic and Foundation in Rochester, Minn., used it to treat a patient with HES who had been eager to find an alternative to current therapies. The effect of imatinib on the patients eosinophil level was astonishing, "almost miraculous," said Gleich. This encouraging result led Gleich and his coworkers to try the drug in four other patients, three of whom responded just as well as the first.
Inspired by early reports of the effectiveness of imatinib in treating patients with HES, Gilliland and his colleagues further evaluated imatinib to discover how it works against the disease. He and others who have studied HES have been thwarted by the lack of clues to the genetics of the disease. But the response of patients with HES to imatinib, a tyrosine kinase inhibitor, suggested a new direction to explore.
Imatinib was designed to zero in on the fusion protein, BCR-ABL, that gives rise to CML. The researchers wanted to know whether the molecular mechanism underlying HES might be similar to that which leads to CML. The existence of BCR-ABL results from a translocation occurring between chromosomes 9 and 22. The protein produced by the fusion gene is a constitutively activated tyrosine kinase that stimulates the overproduction of myeloid cells, especially neutrophils. Imatinib targets the BCR-ABL protein and shuts down production of the leukemic cells. The drug also is able to inhibit four other tyrosine kinases, including kit and platelet-derived growth factor receptor (PDGFR).
In some of the patients with HES who responded to imatinib, Gillilands group detected an 800-kb deletion in chromosome 4 that fused together two genesa newly discovered gene called Fip1-like 1 (FIP1L1) and the PDGFR-alpha (PDGFRA) gene. The resulting fusion gene, FIP1L1PDGFRA, expresses the normally silent PDGFRA tyrosine kinase.
Serendipity played a role in this discovery. As Gilliland pointed out, "we werent looking for it [this type of mutation] because it had never been reported. We more or less just stumbled into it." But this mutation in which a chromosomal deletion fuses two genes together to yield the gain of function of a protein may be a novel way for other cell types to become malignant as well, he said.
Why would such a cancer-causing mechanism have eluded detection until now? Although an 800-kb deletion may sound large, it can easily be missed by any of the typical strategies used to screen for chromosomal deletions, said Gilliland. To address this situation he and his coworkers are developing a method for screening small deletions using DNA from all types of solid tumors and hematologic malignancies.
Now that they know what to look for, said Gilliland, researchers may find similar gain-of-function deletions in other tumors. This could be a boon to cancer researchers working to develop new targeted therapies because gain-of-function mutations are relatively easier targets for drug therapy, he explained. "Clinical experience so far has shown that its much more difficult to replace the lost function of a gene than it is to target a gain of function with a small molecule such as imatinib."
Another intriguing observation from this research is that a much lower dose of imatinib is needed to control HES than to control CMLan average of about 100 mg per day for HES versus 400 mg for CML. Gilliland noted that The FIP1L1PDGFRA fusion protein is about 100-fold more sensitive to imatinib than is either BCR-ABL or the native PDGFRA protein. He theorizes that the fusion of PDGFRA to FIP1L1 changes the conformation of the imatinib binding site and enhances its affinity for the inhibitor.
As with any monotherapy, the potential for resistance to develop against the drug is a concern. And indeed one of the patients treated by Gillilands group developed resistance to imatinib after initially responding. The researchers were able to identify a resistance mutation in this patient and subsequently have shown that resistance can be overcome by using an alternative kinase inhibitor. "This shows that we have proof of principle that we can override resistance by using combinations of drugs, similar to how HIV is treated," Gilliland said.
Not all patients who responded to imatinib carry the mutant gene. It may be that these patients have a mutation in another kinase gene that imatinib is targeting, said Gilliland. The researchers are continuing to look for such mutations that possibly may involve a chromosomal deletion similar to the one that formed FIP1L1-PDGFRA. They also hope to discover the mechanisms at work in the patients with HES who do not respond to imatinib.
These results, said Jorge Cortes, M.D., associate professor of medicine at the University of Texas M. D. Anderson Cancer Center, Houston, and one of Gillilands coauthors, emphasize the fact that translational research is not a one-way street. Not only do observations in the laboratory lead to advances in the clinic, said Cortes, but clinical results can provide new insights at the laboratory bench.
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