14 March 2008
Computational Biology Center
Memorial Sloan-Kettering Cancer Center
CML represents the first human cancer in which molecularly targeted therapy leads to a dramatic clinical response. Imatinib mesylate (Gleevec, STI571) is a potent inhibitor of the BCR-ABL fusion oncogene that drives the leukemia, and induces remission in all stages of the disease. Although CML represents one of the most well studied cancers, several critical questions remain. (i) CML is associated with the BCR-ABL oncogene, but the total number of mutations necessary to initiate the disease is unknown. Is the BCR-ABL oncogene sufficient to cause chronic phase CML? (ii) In most patients imatinib fails to eliminate residual disease, which has been shown to be part of the stem cell compartment. What is the response of leukemic stem cells to imatinib therapy? (iii) A substantial fraction of patients evolves point mutations in the ABL kinase domain leading to treatment failure. What are the dynamics of resistance? (iv) Disease progression has been reported to correlate with an expansion of leukemic stem cells or progenitors. In which cellular compartment do mutations arise that drive progression to blast crisis? (v) The second-generation ABL kinase inhibitors dasatinib and nilotinib are entering clinical trials. What is the dynamics of treatment response to those drugs? In this talk, I will discuss theoretical and experimental approaches to answer these questions.
current theory lunch schedule