Heat shock protein 90 antagonist-based therapy of mantle cell lymphoma

基于热休克蛋白 90 拮抗剂的套细胞淋巴瘤治疗

• 批准号: 7902097
• 负责人: KAPIL BHALLA
• 金额: $ 31.13万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-08 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7902097
• 关键词: 17-(Allylamino)-17-demethoxygeldanamycin; Acetylation; Ansamycin Antineoplastic Antibiotic; Apoptosis; Apoptotic; Attenuated; B lymphoid malignancy; B-lymphocyte Cancer; Benzoquinones; Binding; Bortezomib; CDK4 gene; Cell-Mediated Cytolysis; Cells; Client; Combined Modality Therapy; Cyclin D1; Cyclin-Dependent Kinase 4; Disease-Free Survival; Endoplasmic Reticulum; Ethylenediamines; Failure; Geldanamycin; Geldanamycin Analogue; Growth; HDAC6 gene; Heat-Shock Proteins 90; Histone Deacetylase Inhibitor; Human; Hydroxamic Acids; In Vitro; Maintenance; Mantle Cell Lymphoma; Mediating; Mediator of activation protein; Molecular; Molecular Chaperones; Molecular Conformation; Patients; Phosphotransferases; Proteasome Inhibitor; Proteins; Proto-Oncogene Proteins c-akt; Relapse; Relative (related person); Signal Transduction; Testing; Toxic effect; Vorinostat; analog; base; biological adaptation to stress; design; endoplasmic reticulum stress; improved; in vivo; inhibitor/antagonist; mouse model; multicatalytic endopeptidase complex; novel therapeutics; protein folding; public health relevance; response; transcription factor; treatment strategy; tubacin; tumor

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：需要新的治疗策略来提高人套细胞淋巴瘤（MCL）的无病生存率。热休克蛋白（hsp） 90是一种atp依赖的分子伴侣，需要适当折叠和维持几种客户蛋白的天然和活性构象。格尔达霉素（GAAs）的类似物，如17-AAG和17-DMAG，抑制hsp90的ATP结合和伴侣功能，导致客户蛋白的错误折叠、多泛素化和蛋白酶体降解。最近的研究表明，GAA治疗降低了hsp90客户蛋白CDK4、c-Raf、AKT和cyclin D1的水平，这些蛋白赋予MCL细胞生长和生存优势。此外，GAA处理减少了内质网应激介质PKR和IRE-11。研究显示，羟肟酸类似物（HA）泛组蛋白去乙酰化酶抑制剂（HDI），如vorinostat （SAHA）或LBH589，可增加MCL细胞中CDK抑制剂p21和p27的水平，诱导几种促凋亡和减弱抗凋亡蛋白，包括AKT和c-Raf。此外，ha - hdi通过抑制HDAC6诱导hsp90乙酰化，从而抑制hsp90的ATP结合和伴侣蛋白功能。这导致多泛素化、蛋白酶体降解和MCL相关的hsp90客户蛋白的消耗，以及诱导MCL细胞的生长停滞和凋亡。已知抑制HDAC6可消除核周聚集体的形成，核周聚集体可隔离和保护未折叠蛋白，从而引发内质网应激反应（UPR）。最近，蛋白酶体抑制剂硼替佐米通过内质网应激增加细胞内未折叠蛋白水平和毒性，被证明在复发的MCL中具有单药活性。基于这些观察所创造的强有力的理论基础，本文提出的研究将验证下述假设：硼替佐米和hsp90拮抗剂（GAA和/或HA-HDI）联合治疗将废除涉及聚合体和er基UPR的保护机制，从而在体外和体内发挥相对选择性的、致命的抗mcl作用。因此，本课题的具体目的是：目的1：确定hsp90抑制剂在培养和原代人MCL细胞中抗肿瘤选择性的分子基础；目的2：确定ha - hdi的vorinostat和LBH589，以及更特异性的HDAC6抑制剂tubacin在培养和原代MCL细胞中的相对抗肿瘤选择性的机制；目的3：确定HA-HDI/hsp90抑制剂介导的硼替佐米诱导的内质网应激消除如何导致HA-HDI/hsp90抑制剂与硼替佐米联合抗mcl的选择性；目的4：测定hsp90拮抗剂17-DMAG或LBH589和/或硼替佐米对小鼠MCL模型的体内抗MCL活性。公共卫生相关性：套细胞淋巴瘤（MCL）是一种高度侵袭性的b淋巴细胞癌。利用培养的和患者来源的MCL细胞，以及MCL小鼠模型，拟议的研究将评估一种新的MCL治疗策略的分子基础和疗效。该策略包括结合热休克蛋白90和蛋白小体抑制剂治疗，旨在靶向MCL细胞中的蛋白质折叠和降解。