New treatment strategies are needed to improve the disease free survival in human mantle cell lymphoma (MCL). Heat shock protein (hsp) 90 is an ATP-dependent molecular chaperone required for the proper folding and maintenance of several client proteins in their native and active conformation. Analogues of geldanamycin (GAAs), e.g., 17-AAG and 17-DMAG, inhibit the ATP binding and chaperone function of hsp90, resulting in misfolding, polyubiquitylation and proteasomal degradation of the client proteins. Recent studies demonstrated that treatment with GAA depleted the levels of the hsp90 client proteins CDK4, c-Raf, AKT and cyclin D1, which confer growth and survival advantage on MCL cells. Additionally, GAA treatment depleted the mediators of endoplasmic reticulum (ER) stress PKR and IRE-11. Treatment with hydroxamic acid analogue (HA) pan-histone deacetylase inhibitor (HDI), e.g., vorinostat (SAHA) or LBH589, was shown to increase the levels of the CDK inhibitors p21 and p27, induce several pro-apoptotic and attenuate antiapoptotic proteins, including AKT and c-Raf, in MCL cells. Furthermore, by inhibiting HDAC6, HA-HDIs induced hsp90 acetylation, which inhibited ATP binding and chaperone function of hsp90. This resulted in polyubiquitylation, proteasomal degradation and depletion of the MCL-relevant hsp90 client proteins, as well as induced growth arrest and apoptosis of MCL cells. Inhibition of HDAC6 is known to abrogate the formation of perinuclear aggresome, which sequesters and protects against unfolded proteins, known to trigger ER stress response (UPR). Recently, the proteasome inhibitor bortezomib, which increases intracellular unfolded protein levels and toxicity through ER stress, was shown to have a single agent activity in relapsed MCL. Based on the strong rationale created by these observations, studies proposed here will test the hypothesis that combined treatment with bortezomib and hsp90 antagonists (GAA and/or HA-HDI) will abrogate the protective mechanisms involving the aggresome and ER-based UPR, thereby exerting a relatively selective, in vitro and in vivo, lethal, anti-MCL effect. Therefore, the specific aims of this proposal are:
AIM 1 : To determine the molecular basis of the anti-tumor selectivity of hsp90 inhibitors in cultured and primary human MCL cells;
AIM 2 : To determine the mechanism(s) of the relative anti-tumor selectivity of the HA-HDIs vorinostat and LBH589, as well as the more specific HDAC6 inhibitor tubacin in cultured and primary MCL cells;
AIM 3 : To determine how HA-HDI/hsp90 inhibitor-mediated abrogation of bortezomib-induced ER stress results in anti-MCL selectivity of the combination of HA-HDI/hsp90 inhibitor with bortezomib;
AIM 4 : To determine the in vivo anti-MCL activity of the hsp90 antagonist 17-DMAG or LBH589 and/or bortezomib against mouse models of MCL.
Mantle cell lymphoma (MCL) is a highly aggressive cancer of B-lymphocytes. Utilizing cultured and patient-derived MCL cells, as well as mouse models of MCL, proposed studies would evaluate the molecular underpinnings and efficacy of a novel therapeutic strategy for MCL. This strategy involves combinations of treatments with heat shock protein 90 and proteosome inhibitors designed to target protein folding and degradation in MCL cells. ? ? ?
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