Bcr-abl kinase inhibition as the basis of therapy for cml

Abstract

Abstract The p210 Bcr-Abl fusion protein is present in virtually all patients with CML and a 185 kD variant is present in approximately 20% of ALL patients. The transforming function of Bcr-Abl requires tyrosine kinase activity of these Bcr-Abl fusion proteins. Thus, Bcr-Abl is an ideal candidate for a molecularly targeted therapeutic agent and an inhibitor of the Bcr-Abl kinase would be predicted to be an effective and selective therapeutic agent for CML. STI571 (formerly CGP57148B), synthesized at Novaris Pharmaceuticals is a potent and specific inhibitor of the Abl kinases and is currently in clinical trials. In a dose-escalating trial all patients in the chronic phase (n=31) have achieved hematologic remissions once therapeutic dose levels were achieved. With prolonged therapy (5 months or greater), a growing fraction of these patients have cytogenetic responses, including several individuals with complete disappearance of the Ph chromosome. STI571 also has remarkable activity as a single agent in CML blast crisis and Ph + ALL patients, however, responses tend not to be durable. As virtually all patients with CML express Bcr-Abl and the Bcr-Abl protein is unique to tumor cells, this disease has provided an ideal opportunity to test the concepts that drugs targeted against a tumor-specific abnormality will have therapeutic utility. Ongoing studies are directed at optimizing the use of this agent.