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: 8298621
• 负责人: KAPIL BHALLA
• 金额: $ 4.72万
• 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 2013-03-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8298621
• 关键词: 17-(Allylamino)-17-demethoxygeldanamycin; 17-(Dimethylaminoethylamino)-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; Health; 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 degradation; protein folding; 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（由申请方提供）：需要新的治疗策略来提高人套细胞淋巴瘤（MCL）的无病生存期。热休克蛋白（HSP）90是一种ATP依赖的分子伴侣，它能使几种客户蛋白正确折叠并维持其天然和活性构象。格尔德霉素（GAA）的类似物，例如，17-AAG和17-DMAG抑制hsp 90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，用GAA处理耗尽了Hsp 90客户蛋白CDK 4、c-Raf、AKT和细胞周期蛋白D1的水平，这些蛋白赋予MCL细胞生长和存活优势。此外，GAA处理耗尽内质网（ER）应激PKR和IRE-11的介质。用异羟肟酸类似物（HA）泛组蛋白脱乙酰酶抑制剂（HDI），例如，vorinostat（SAHA）或LBH 589显示在MCL细胞中增加CDK抑制剂p21和p27的水平，诱导几种促凋亡蛋白和减弱抗凋亡蛋白，包括AKT和c-Raf。HA-HDIs通过抑制HDAC 6诱导hsp 90乙酰化，从而抑制hsp 90的ATP结合和分子伴侣功能。这导致多聚泛素化，蛋白酶体降解和消耗的MCL相关的热休克蛋白90客户端蛋白，以及诱导生长停滞和MCL细胞凋亡。已知HDAC 6的抑制消除核周攻击体的形成，所述核周攻击体隔离并保护免受已知触发ER应激反应（UPR）的未折叠蛋白质。最近，蛋白酶体抑制剂硼替佐米（通过ER应激增加细胞内未折叠蛋白水平和毒性）显示在复发性MCL中具有单一药物活性。基于这些观察结果产生的强有力的理论基础，本文提出的研究将检验以下假设：硼替佐米和hsp 90拮抗剂（GAA和/或HA-HDI）联合治疗将消除涉及攻击性基因组和基于ER的UPR的保护机制，从而发挥相对选择性的体外和体内致死性抗MCL作用。因此，本提案的具体目的是：目的1：确定hsp 90抑制剂在培养的和原代人MCL细胞中的抗肿瘤选择性的分子基础;目的2：确定HA-HDI伏立诺他和LBH 589以及更特异性的HDAC 6抑制剂微管菌素在培养的和原代MCL细胞中的相对抗肿瘤选择性的机制;目的3：确定HA-HDI/hsp 90拮抗剂介导的硼替佐米诱导的ER应激的消除如何导致HA-HDI/hsp 90抑制剂与硼替佐米的组合的抗MCL选择性;目的4：确定hsp 90拮抗剂17-DMAG或LBH 589和/或硼替佐米针对MCL小鼠模型的体内抗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淋巴细胞癌症。利用培养的和患者来源的MCL细胞，以及MCL的小鼠模型，拟议的研究将评估MCL的新治疗策略的分子基础和疗效。该策略涉及热休克蛋白90和蛋白酶体抑制剂的组合治疗，该蛋白酶体抑制剂旨在靶向MCL细胞中的蛋白质折叠和降解。