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 依赖性分子伴侣，是多种客户蛋白正确折叠和维持其天然和活性构象所必需的。格尔德霉素 (GAAs) 类似物，例如 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 治疗可降低 hsp90 客户蛋白 CDK4、c-Raf、AKT 和细胞周期蛋白 D1 的水平，从而赋予 MCL 细胞生长和生存优势。此外，GAA 治疗耗尽了内质网 (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)，例如伏立诺他 (SAHA) 或 LBH589 治疗，显示可增加 CDK 抑制剂 p21 和 p27 的水平，诱导多种促凋亡和减弱抗凋亡蛋白，包括 MCL 细胞中的 AKT 和 c-Raf。此外，通过抑制 HDAC6，HA-HDI 诱导 hsp90 乙酰化，从而抑制 ATP 结合和 hsp90 的伴侣功能。这导致 MCL 相关 hsp90 客户蛋白的多泛素化、蛋白酶体降解和耗尽，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，该聚集体可隔离并保护未折叠蛋白，从而触发 ER 应激反应 (UPR)。最近，蛋白酶体抑制剂硼替佐米（bortezomib）通过内质网应激增加细胞内未折叠蛋白水平和毒性，被证明对复发性 MCL 具有单药活性。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 hsp90 拮抗剂（GAA 和/或 HA-HDI）联合治疗将消除涉及攻击性和基于 ER 的 UPR 的保护机制，从而发挥作用具有相对选择性、体外和体内致死性的抗 MCL 作用。因此，本提案的具体目标是： AIM 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；目标 2：确定 HA-HDI 伏立诺他和 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；目标 3：确定 HA-HDI/hsp90 抑制剂介导的硼替佐米诱导的 ER 应激消除如何导致 HA-HDI/hsp90 抑制剂与硼替佐米组合的抗 MCL 选择性；目的4：确定hsp90拮抗剂17-DMAG或LBH589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。拟议的研究将利用培养的和患者来源的 MCL 细胞以及 MCL 小鼠模型来评估 MCL 新型治疗策略的分子基础和功效。该策略涉及热休克蛋白 90 和蛋白酶体抑制剂的联合治疗，旨在针对 MCL 细胞中的蛋白质折叠和降解。