Abstract
Abstract 1888Poster Board I-911 Introduction:Abnormalities in JAK2 and FLT3 kinases are reported in various hematological malignancies and may underlie the pathogenesis of these diseases. An activating mutation of JAK2, namely JAK2V617F is the most common mutation in bcr-abl-negative chronic myeloproliferative disorders (MPDs). Activation of wild type JAK2 has been reported in Hodgkin lymphoma (HL) and primary mediastinal large cell Non-Hodgkin lymphomas (NHL) due to loss of Suppressor of Cytokine Signaling (SOCS)-1 gene. Abnormalities in FLT3 are present in ∼30% of acute myelogenous leukemias (AML). SB1518 is a potent inhibitor of both JAK2 (IC50 = 22 nM) and its JAK2V617F mutant (IC50 = 19 nM) as well as FLT3 (IC50 = 22 nM) and it mutant D835Y (IC50 = 6 nM). As a consequence, SB1518 inhibits the proliferation of human leukemia and lymphoma cell lines dependent on either JAK2 or FLT3 activation (IC50 =35–240 nM), and has antitumor activity in nude mouse models of FLT3- (MV4-11) or JAK2-dependent (BaF3-JAK2V617F) leukemia. SB1518 is currently being evaluated in Phase 1 clinical trials for advanced leukemias, MPDs and lymphoma. We describe here the development and assessment of biochemical biomarkers to assess the pharmacodynamic (PD) efficacy of SB1518 in the phase I clinical trials. Methods and Results:Sensitive flow cytometric and quantitative Western-blot assays were developed for measuring downstream JAK2 and FLT-3 signaling; namely STAT5/3 phosphorylation in tumor tissue, fixed cells from whole blood or lysed PBMCs. These assays were validated by demonstrating target inhibition after ex vivo treatment of PBMCs from healthy human donors and in blood cells and tumor tissue after oral dosing of normal and tumor bearing nude mice with SB1518. Initial data obtained from analysis of whole blood and PBMCs from patients treated with SB1518 in the ongoing Phase 1 clinical trials demonstrate target inhibition even at the lowest dose level of 100 mg/day on the first day of oral dosing. Conclusion:In summary, we have developed and quantitative biomarker assays and applied them to demonstrate PD target efficacy of SB1518 in animal tumor models as well as patients in ongoing phase 1 clinical trials. Disclosures:Hart:S*BIO PTE LTD: Employment, Equity Ownership. Goh:S*BIO PTE LTD: Employment. Tan:S*BIO PTE LTD: Employment. Chithra:S*BIO PTE LTD: Employment. Wood:S*BIO PTE LTD: Employment.
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