As scientists uncover the precise molecular mechanisms that underlie effective cancer treatments, they gain invaluable insight into why predominantly successful treatments fail for some patients. A new study published in the February issue of Cancer Cell reveals how detailed information about the action of an existing drug was used to design a compound that is effective against some notoriously treatment resistant cancer cases.
Despite the resounding success of anticancer drug imatinib (Gleevec) as a treatment of chronic myeloid leukemia (CML), a small but growing number of patients develop resistance to the drug and relapse. Imatinib inhibits the activity of Bcr-Abl, a protein that is abnormally active in most CML patients. Relapse and resistance to imatinib in patients with advanced disease is linked to the emergence of additional mutant forms of Bcr-Abl that are not inhibited by imatinib.
A group led by Dr. James D. Griffin from the Dana-Farber Cancer Institute working with scientists at Novartis Pharma AG in Switzerland used data obtained from structural examination of the molecular interaction between imatinib and Abl to design AMN107, a compound that has a stronger and more complete molecular association with Abl. AMN107 effectively blocked proliferation of Bcr-Abl dependent cells derived from CML patients and was an even more potent inhibitor of Bcr-Abl than imatinib. Importantly, AMN107 inhibited the growth of cells expressing many Bcr-Abl mutants that were resistant to imatinib and oral administration of AMN107 prolonged survival in imatinib-resistant CML mouse models.
Phase I clinical trials with AMN107 have just started. "If human clinical trials validate the effectiveness of AMN107 demonstrated in the preclinical studies reported here, it may be possible to either use AMN107 in selected patients with imatinib resistance, or to use both agents together, simultaneously or sequentially," says Dr. Griffin. The researchers are hopeful that combined therapy may suppress emergence of treatment resistant Abl mutants and that availability of novel, high potency, Abl tyrosine kinase inhibitors will usher in a new generation of clinical studies that may result in additional major advances in the therapy of hard to treat leukemia.