Our lab is primarily focused on targeted therapy approaches to treating human hematologic malignancies. Much of our past work has focused on chronic myeloid leukemia (CML), a disease of the hematopoietic pluripotent stem cell, which can be effectively treated with small molecule tyrosine kinase inhibitors (TKIs) such as imatinib (Gleevec), which selectively targets the pathologically activated BCR-ABL tyrosine kinase. We initially dissected molecular mechanisms of resistance to imatinib resistance, and exploited this understanding to preclinically identify and clinically test novel compounds for the treatment of imatinib-resistant disease. Through a collaborative effort with Bristol-Myers Squibb, we identified dasatinib (Sprycel) as a promising second generation TKI, and spearheaded the first clinical studies with this agent, which led to its approval by the US FDA and numerous other regulatory agencies in 2006. We continue to work toward a better understanding of resistance mechanisms to BCR-ABL TKIs, and to pinpoint the molecular features of BCR-ABL kinase activity that enable it to confer a state of “oncogene addiction” and thereby render it a highly effective target.

Much of our current work is focused on acute myeloid leukemia (AML), the most common type of leukemia in adults. Recently, potent inhibitors of the FLT3 kinase have demonstrated impressive clinical activity in a substantial proportion of acute myeloid leukemia (AML) patients who harbor activating mutations in this kinase, but in the vast majority of cases, the disease relapses quickly. We identified a small number of drug-resistant point mutations in the kinase domain in most samples obtained from patients whose disease developed resistance to treatment. This work has led to the identification and clinical investigation of several new FLT3 TKIs. Translational studies with samples obtained from these patients are ongoing. Current efforts are aimed at characterizing and circumventing other mechanisms of resistance to FLT3 TKIs and better defining the clonal hierarchy of resistant disease. Basic and translational studies are also ongoing with promising investigational therapies that target proteins such as BRD4, IDH1/2.