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Targeted Therapy of Hematologic Malignancies Background:Translational research seeks to apply molecular understanding of the pathophysiology of disease to the development of new effective therapies. Chronic myeloid leukemia (CML) represents the first of an increasing number of human malignancies to be successfully treated with a selective small molecule tyrosine kinase inhibitor (STI571; imatinib; Gleevec), which targets the CML-specific fusion oncogene BCR-ABL. Resistance to imatinib is nearly always associated with restoration of BCR-ABL kinase activity, most often through selection for cells harboring BCR-ABL kinase domain mutations that impair drug binding yet preserve kinase activity. Resistant disease can respond to an alternative BCR-ABL inhibitor (BMS-354825; dasatinib; Sprycel) in most cases, but one mutation appears to be highly resistant to both drugs, and is a leading cause of relapse in patients treated with dasatinib. This mutation is sensitive in vitro to an Aurora kinase inhibitor. Major Goals: (i) improve treatment outcomes with kinase inhibitors by utilizing combination therapy and incorporating biomarkers of efficacy (ii) unravel mechanisms of cell death in response to kinase inhibition and molecular mechanisms that enable survival of CML stem cells despite kinase inhibitor therapy (iii) identify other hematologic malignancies that may be candidates for effective treatment with tyrosine kinase inhibitors Ongoing Research: Optimizing the timing of targeted therapy for human malignancy: The optimal timing of targeted therapies (sequential versus combinatorial) for the successful treatment of human malignancies is undetermined. We analyzed blood from CML patients who relapsed after sequential treatment with imatinib then dasatinib. All patients acquired new BCR-ABL kinase domain mutations, often in clones already bearing imatinib-resistant mutations (compound mutants). Initial combination kinase inhibitor therapy may be a better general approach to improve response duration in cancer. Preliminary evidence suggests that VX-680, an Aurora kinase inhibitor, is effective against dasatinib-resistant mutants, and a clinical trial evaluation of an Aurora kinase inhibitor for dasatinib-resistant cases is ongoing. Optimizing treatment outcomes with targeted therapies by utilizing biomarkers: A preliminary analysis of cell lysates in patients treated with dasatinib reveals a strong correlation between the depth of BCR-ABL inhibition and the depth of response. A flow-based method that can quantify the degree of BCR-ABL inhibition in patients is currently under development, and will be validated in a clinical trial. Defining mechanisms of cell death in response to kinase inhibitors: Kinase inhibitor therapy results in death of committed hematopoietic cells in CML patients through poorly understood mechanisms, yet primitive quiescent CML stem cell progenitors persist. Exposure of CML cell lines to high concentrations of kinase inhibitors for as short as 20 minutes can lead to profound cell death; this phenomenon can also be observed in other kinase-driven cell lines. An analysis of cell death mechanisms is ongoing, and will be performed in primary CML cells. Selected Publications: Shah, NP, FY Lee, R Luo, Y Jiang, M Donker and C Akin. 2006. Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activation mutation that triggers neoplastic growth in the majority of patients with systemic mastocytosis. Blood 108:286-291. Talpaz, M, NP Shah, H Kantarjian, N Donato, J Nicoll, R Paquette, J Cortes, S O'Brien, C Nicaise, E Bleickardt, MA Blackwood-Chirchir, V Iyer, T-T Chen, F Huang, AP Decillis and CL Sawyers. 2006. Activity of the ABL Kinase Inhibitor Dasatinib in Imatinib-Resistant Philadelphia Chromosome Positive Leukemias. NEJM : 354:2531-2341 . Young, MA, NP Shah, LH Chao, M Seeliger, ZV Milanov, WH Biggs, DK Treiber, HK Patel, PP Zarrinkar, DJ Lockhart, CL Sawyers and J Kuriyan. 2006. Structure of the kinase domain of imatinib-resistant ABL mutant in complex with the Aurora kinase inhibitor VX-680. Cancer Res 66:1007-1014. Carter, TA, LM Wodicka, NP Shah, AM Velasco, MA Fabian, DK Treiber, ZV Milanov, CE Atteridge, WH Biggs, PT Edeen, M Floyd, JM Ford, RM Grotzfeld, S Herrgard, DE Insko, SA Mehta, HK Patel, W Pao, CL Sawyers, H Varmus, PP Zarrinkar and DJ Lockhart. 2005. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci USA : 102:11011-11016. Michor, F, TP Hughes, Y Iwasa, S Branford, NP Shah, CL Sawyers and MA Nowak. 2005. Dynamics of chronic myeloid leukemia. Nature 435:1267-1270. Burgess, MR, BJ Skaggs, NP Shah, FY Lee and CL Sawyers. 2005. Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance. Proc Natl Acad Sci USA :102:3395-3400. Shah, NP, C Tran, FY Lee, D Norris, P Chen and CL Sawyers. 2004. Overriding imatinib resistance with a novel ABL inhibitor. Science 305:399-401. Shah, NP, JM Nicoll, B Nagar, ME Gorre, RL Paquette, J Kuriyan and CL Sawyers. 2002. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2:117-125.
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