New Study on Gleevec Resistance Reinforces Principle of Targeted Therapy for Cancer Treatment

A new drug may overcome Gleevec resistance in late-stage chronic myeloid leukemia (CML) patients, according to findings reported in the February 2005 issue of the journal Cancer Cell. A key conclusion associated with the study is that the new drug acts on the same molecular abnormality targeted by Gleevec, indicating that this previously identified signaling pathway is consistently central to disease pathogenesis.

"This implies that targeted therapy is the strategy of choice in the fight against CML specifically and reinforces the potential of this strategy for other cancers as well," said Brian Druker, M.D. "As more drugs are developed that succeed within this paradigm, it becomes increasingly likely that this will lead to significantly expanded options for patients."

Druker and colleagues published a review of the new study and its implications in the same issue of Cancer Cell. Druker is the JELD-WEN Chair of Leukemia Research at the Oregon Health & Science University Cancer Institute and a Howard Hughes Medical Institute Investigator.

Druker originally collaborated with pharmaceutical company Novartis to develop Gleevec into a successful treatment for CML. In 2001, the Food and Drug Administration (FDA) broke a record for cancer therapy approval by fast-tracking Gleevec, approving it in less than three months.

About 6,000 Americans each year are diagnosed with CML, a cancerous blood disease characterized by an excessive production of white blood cells. Currently about 95 percent of these CML patients achieve a lasting response with Gleevec therapy. Gleevec specifically targets the enzyme produced by the Bcr-Abl gene that causes production of excessive white blood cells.

While relapses are relatively uncommon in newly diagnosed patients treated with Gleevec, they are the rule in patients with more advanced disease. To date, scientists have identified at least 30 different mutations within the Bcr-Abl domain that may play a role in this Gleevec sensitivity.

As reported in Cancer Cell, researchers at Novartis Pharmaceuticals in Basel, Switzerland, approached the challenge of resistance by designing a more potent form of Gleevec and then worked with researchers at Dana-Farber Cancer Institute to test the compound. The resulting drug, AMN107, which is still in clinical trials, is approximately 20-fold stronger than Gleevec. For patients, this translates into improved inhibitory activity against many of the identified Bcr-Abl mutations.

Druker and colleagues also are investigating the efficacy of AMN107 and companion drugs designed to overcome Gleevec resistance. OHSU will be a site of associated clinical trials in coming months. Depending on the outcome of clinical trials, a potentially effective new therapeutic approach may be to use AMN107, Gleevec and chemically similar drugs in a cocktail to prohibit or delay the onset of acquired drug resistance in patients with advanced CML, said Druker.

An equally important outcome of this work, he noted, is the demonstration of how quickly an understanding of the molecular mechanism of Gleevec resistance has translated into new treatment.

"This illustrates the speed at which new drug development to fight cancers can occur under the right set of scientific and funding circumstances," said Druker.