The deregulated activity of the Bcr-Abl tyrosine kinase (TK) is a client protein of heat shock protein (hsp) 90 and the molecular hallmark of chronic myeloid leukemia (CML). Accordingly, lowering the levels of Bcr-Abl, e.g., by hsp90 inhibitor 17-AAG or by inhibiting the Bcr-Abl TK activity by imatinib mesylate (IM; Gleevec) inhibits the growth and induces apoptosis of CML cells. Although IM is clinically very active in the chronic phase of CML, resistance to IM due to mutations or amplification of Bcr-Abl results in poor clinical outcome, especially in the advanced stages of CML and acute lymphoid leukemia (ALL). Preliminary studies from our laboratory have demonstrated that treatment with hydroxamic acid analogue (HA) histone deacetylase inhibitors (HDIs) SAHA (suberoylanilide hydroxamic acid), LAQ824 and LBH589 attenuates the mRNA levels and, by inhibiting hsp90, promotes the degradation of wild type and mutant Bcr-Abl, which triggers apoptosis of the IM-sensitive and IM-refractory Bcr-Abl expressing leukemia cells. Additionally, co-treatment with HDI enhanced apoptosis induced by IM and the novel Bcr-Abl inhibitor AMN107, as well as by 17-AAG and the death ligand TRAIL. The overall hypothesis motivating the proposed studies is that by inhibiting hsp90 and attenuating the levels of not only wild type but also mutant Bcr-Abl, as well as by inducing pro-death (Bak, Bax and Bim) and downregulating pro-survival proteins (Bcl-xL, XIAP, AKT and c-Raf), treatment with the HA-HDIs would sensitize IM-sensitive and IM-refractory CML or ALL cells to IM, AMN107, BMS354825, 17-AAG and TRAIL.
The aims of the proposal are: 1. To determine the growth inhibitory and apoptotic effects, and their molecular determinants, of the HA-HDIs, administered alone or in combination with IM or AMN107 in the wild-type or mutant Bcr-Abl expressing, IM-sensitive or IM-resistant, cultured and primary leukemia cells. The anti-leukemia efficacy of these combinations would also be evaluated in a conditional transgenic mouse model of Bcr-Abl-induced acute leukemia. 2. To determine the growth inhibitory and apoptotic effects, and their molecular determinants, of the combinations, of HA-HDIs with the dual Bcr-Abl/Src inhibitor BMS354825 in the wild type or mutant Bcr-Abl expressing cultured and primary leukemia cells. 3. To determine the effects of co-treatment with HA-HDIs with 17-AAG on the chaperone function of hsp90 and on the growth arrest and apoptosis of the wild type or mutant Bcr-Abl expressing, IM-sensitive or IM-resistant, cultured and primary leukemia cells. 4. To determine the apoptotic effect of co-treatment with the HA-HDIs and TRAIL, and its molecular determinants, in the wild type or mutant Bcr-Abl expressing cultured and primary leukemia cells Significance: The pre-clinical data generated by these studies should guide the implementation of phase I and II clinical trials of the HA-HDI-based novel combinations and assist in identifying the predictive biomarkers for these agents in patients with wild type or mutant Bcr-Abl expressing, IM-sensitive or IM-resistant leukemia.
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