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Sprycel circumvents Glivec resistance in chronic myeloid leukemia

Dasatinib ( Sprycel ) reverses the signs and symptoms of patients whose chronic myeloid leukemia has failed to respond to Imatinib ( Gleevec / Glivec ), which is considered the standard of treatment for the disorder.

In a study published in The New England Journal of Medicine ( NEJM ), Howard Hughes Medical Institute ( HHMI ) researchers at the University of California, Los Angeles ( UCLA ), and colleagues at M.D. Anderson Cancer Center and Bristol-Myers Squibb in Princeton, reported data from phase I human clinical trials of the compound, Dasatinib.

. The studies published in NEJM indicate that Dasatinib can be used to overcome Imatinib resistance in patients who have chronic myeloid leukemia ( CML ).
Patients enrolled in the study had experienced a worsening of the disease or intolerance when treated with Imatinib.

Study leader, HHMI investigator Charles L. Sawyers, and colleagues at UCLA's Jonsson Comprehensive Cancer Center, reported that Dasatinib successfully circumvented Imatinib resistance in 68 of 84 patients treated with the drug during phase I clinical trials at UCLA and M.D. Anderson Cancer Center. Resistance to Gleevec develops when patients acquire mutations in an enzyme that is targeted by Imatinib.

" The studies provide immediate hope for patients in whom CML cells have developed resistance to Imatinib," wrote HHMI investigator Brian J. Druker of Oregon Health and Science University in an accompanying editorial in NEJM.

Speaking about the NEJM study, Sawyers said, " Our study examined patients in all phases of CML, including the chronic phase, the accelerated phase, and blast crisis. The patients responded quite well to this drug, and we observed no serious side effects. Their responses to the drug are durable, and the drug works in advanced stages of the disease, including blast crisis."

Of the 84 patients enrolled in the study, 40 had chronic-phase CML; 11 had accelerated-phase CML; 23 had myeloid blast crisis; and 10 had lymphoid blast crisis.
Drug dosages were fine-tuned for each patient based on detailed studies that examined how well the drug inhibited its target, a technique that was pioneered by Sawyers's group for use in earlier studies in mice.
Another novel facet of the study, Sawyers said, is that each patient's resistance-enhancing mutation was sequenced by Bristol-Myers Squibb ( BMS ) researchers. This provided a wealth of information about the type of mutation carried by each patient, and allowed the researchers to correlate how the drug responded to each type of mutation.

" Every single patient who was predicted to be sensitive to Dasatinib based on the genotyping studies had a clinical response," Sawyers said.

The identification of Dasatinib as a lead compound was a direct result of researchers' learning the molecular explanation for why patients develop resistance to Imatinib. Sawyers noted that just as Gleevec was developed as a molecularly targeted inhibitor, the next generations of kinase inhibitors, which include Dasatinib, are being refined and improved by structural biology studies that show how the drugs "fit" with their target, and how mutations alter the shape of that target.

In this case, the target of both Imatinib and Dasatinib is the Abelson tyrosine kinase ( ABL ), an enzyme that becomes overactivated by a chromosomal mix-up that occurs during blood cell development.
The genes ABL and BCR, which are located on different chromosomes, become fused and express a hybrid BCR-ABL enzyme that is always active.
The hyperactive BCR-ABL, in turn, drives the overproliferation of white blood cells that is the hallmark of CML.
Dasatinib differs from Imatinib in that it is a "sloppier inhibitor" that does not hold its target to such tight structural constraints.

There are currently about 50 known Imatinib-resistance mutations, each of which hampers Gleevec's ability to bind to its target, the ABL kinase.
In the case of both Imatinib and Dasatinib, there appears to be one particular mutation, known as T315I, which does not respond to either therapy. " That mutation will likely require a different drug, and researchers are working on that now," said Sawyers.

Source: Howard Hughes Medical Institute, 2006