Gleevec, a drug regarded by many as having "wonder drug" capabilities in the treatment of chronic myelogenous leukaemia (CML) and other cancers, has been revealed as having shortcomings in that some patients have undergone a relapse after building a resistance to the drug. For others with the advanced stage of the disease, the drug has failed to produce durable remissions.
Now however, scientists have discovered that a molecular understanding of resistance has rapidly led to a new generation of drugs that might prove even more effective than Gleevec.
Two new studies report that a new compound, known as AMN107, may one day offer a more potent alternative for treating patients with acquired Gleevec resistance and others with advanced CML.
In its original conception Gleevec works in CML patients by selectively deactivating Bcr-Abl, the abnormal tyrosine kinase protein that triggers rapid growth of leukemic cells and was hailed as the first approved drug to directly inhibit the activity of an enzyme known to cause uncontrolled cell growth, and it has been highly successful for many patients.
But scientists soon recognized that some patients develop mutations in the Bcr-Abl protein that drastically reduces Gleevec's effectiveness.
To overcome this resistance to Gleevec, scientists are designing new compounds and AMN107 is one such drug produced by Novartis Pharmaceuticals in Basel, Switzerland in collaboration with investigators at the Dana Farber Cancer Institute.
Basically AMN107 retains half the chemical makeup of Gleevec, while the other half was designed to create a tighter link to Bcr-Abl, thus increasing potency and potentially overcoming resistance due to mutations in Bcr-Abl.
Scientists at the Oregon Health and Science University in Portland compared the potency of the new compound against Gleevec using a panel of cell lines expressing 16 different Gleevec-resistant, mutant versions of Bcr-Abl and their results showed that AMN107 was at least 20 times more potent than Gleevec against most of the resistant mutants.
Thomas O'Hare, a research specialist in Gleevec pioneer Brian Druker's laboratory at the Oregon Health and Science University Cancer Institute says the results show that 15 of the 16 mutants were sensitive to AMN107, while one mutant remained insensitive and would require a different, as yet undiscovered, inhibitor. The results were equally impressive when the other leading drug in this field, a Bristol-Myers Squibb compound called BMS-354825, was also investigated. The team say that the data indicates that AMN107 is a highly active Bcr-Abl inhibitor that may have clinical utility in patients with Gleevec-refractory CML which is great news for patients. They believe that having several safe and effective drugs available is the key to controlling acquired drug resistance in CML.