New Drugs Target Treatment-Resistant Leukemia

By Jeffrey Norris, UCSF Science Cafe | November 9, 2006

The drug imatinib (Gleevec) is generally considered to be the most significant new entrant in the armamentarium of anticancer drugs in the past 20 years. Its approval in May 2001 was the cover story of Time magazine. In patients whose cancers had grown despite earlier treatment, studies showed that imatinib eliminated signs of cancer in most patients with a type of leukemia called CML or with a type of stomach cancer called GIST. The drug was the first approved cancer treatment that works by specifically inhibiting the activity of a protein known as a kinase. Gleevec attaches to and blocks the growth-stimulating activity of a kinase called BCR-ABL.

Unfortunately, many patients initially treated successfully with imatinib have since relapsed. Neil Shah, a hematologic oncologist who came to UCSF from UCLA earlier this year, was among a group of researchers who first identified the molecular reasons -- specific mutations -- why imatinib-resistant disease develops. Any one of more than 40 mutations allows the intended target protein -- BCR-ABL -- to change shape and evade inhibition by the drug.

Shah's work led him to test new drug candidates targeted against BCR-ABL for activity against imatinib-resistant mutants. While conducting research in the laboratory of oncologist Charles Sawyers at UCLA, he first began investigating experimental treatments in cultured cell lines and tumor cells in the laboratory, paying careful attention to the susceptibility of cancerous cells that harbor imatinib-resistant BCR-ABL mutations.

Read more at Jeffrey Norris, UCSF Science Cafe