New research shows that the delicate balance between maximum clinical impact and toxicity may not be quite as fragile as scientists had previously believed.
The study, published by Cell Press in the December issue of the journal Cancer Cell, is likely to have a major impact on the future design and implementation of targeted cancer therapies.
Small molecule tyrosine kinase inhibitors, such as imatinib (Gleevec) which targets the BCR-ABL kinase associated with chronic myeloid leukemia (CML), have prolonged half-lives in patients and provide almost continuous inhibition of their targets when administered once daily. It was generally assumed that prolonged target inhibition was required to achieve clinical activity with such inhibitors. This assumption was a major driving force in both drug discovery efforts where many agents with short half-lives were abandoned prior to clinical development and also in the design of dosing schedules.
Desatinib is a second generation BCR-ABL kinase inhibitor with greater potency but a much shorter half-life than imatinib and all other approved kinase inhibitors. "The clinical development of dasatinib initially proceeded using a twice-daily dosing schedule with the goal of providing continuous target coverage," explains lead study author, Dr. Neil P. Shah from the University of California, San Francisco School of Medicine. Dr. Shah was the lead author of a clinical study, recently published in the Journal of Clinical Oncology, which found that the clinical benefit of dasatinib was equivalent when dosed once daily, and importantly, tolerability was superior to the twice-daily schedule.