Targeting hard-to-treat cancers

For most patients with chronic myelogenous leukemia (CML), chemotherapy with imatinib results in a complete hematologic and cytogenetic response. However, patients who acquire drug-resistant CML have a poor prognosis. Ellen Weisberg and colleagues recently identified the mechanism for imatinib resistance and have designed a new drug that may overcome the problem.1

The Philadelphia chromosome is uniformly present in CML. A hybrid gene on the chromosome, Bcr-Abl, codes for an abnormal tyrosine kinase protein that triggers the uncontrolled proliferation of CML cells. By inhibiting the tyrosine kinase protein, imatinib suppresses the proliferation and induces apoptosis in Bcr-Abl positive cell lines. Resistance to imatinib is associated with mutations in the protein Bcr-Abl that reduce the effectiveness of treatment.2^,3 After examining the detailed structure of the binding mechanism of imatinib to Bcr/Abl, the researchers were able to design a drug, AMN107, that induced a 10- to 50-fold greater inhibition of the gene in in-vitro experiments with human CML cell lines. More important, they demonstrated that AMN107 can inhibit mutant Bcr-Abl proteins that are resistant to imatinib both in vitro, in human cells, and in vivo, in experiments using mice. Finally, they found no evidence of drug toxicity.

The authors1 state that AMN107 is poised to be studied in phase I clinical trials. It is hoped that this drug will prove useful in overcoming the deadly problem of drug resistance and that the methods used by these authors will prove to be a model for the design of future cancer drugs.