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.
Thanks to the effort of Shah and colleagues, another drug - dasatinib - was approved earlier this year for the treatment of CML when imatinib fails. "We were able to go from laboratory testing on imatinib-resistant cell lines in 2003 to FDA approval in 2006. That makes me very hopeful about the future development and testing of new cancer treatments in the coming years," Shah says.
A handful of BCR-ABL mutations still resist dasatinib, so Shah has been investigating another kinase inhibitor drug candidate known as an Aurora kinase inhibitor. This inhibitor can wipe out mutants that even dasatinib cannot kill. The first phase of clinical trials is underway. Participating academic medical centers include UCLA, UCSF and Memorial Sloan-Kettering Cancer Center. As with current AIDS treatments, multiple therapies may ultimately prove to be the most effective against leukemias and other cancers, Shah suggests.