P-3: Characterization and Targeting of the Cytoprotective Chaperone, HSP27

P-3：细胞保护伴侣 HSP27 的表征和靶向

• 批准号: 8130548
• 负责人: MARTIN GLEAVE
• 金额: $ 27.47万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8130548
• 关键词: Affect; Androgens; Antibodies; Apoptosis; Apoptosis Regulator; Aspirate substance; Bone Marrow; Castration; Cell Death; Cell Proliferation; Cell Survival; Cells; Cellular Stress; Client; Clinical Research; Clinical Trials; Complement; Correlative Study; Coupled; Cytoprotection; Data; Development; Dose; Dose-Limiting; Drug Kinetics; Effectiveness; Enrollment; Evaluable Disease; Generations; Genes; Grant; HSPB1 gene; Heat Shock Protein 27; Hormones; Hour; In Vitro; Interleukin-6; Intravenous infusion procedures; LNCaP; Ligands; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Molecular Chaperones; Molecular Profiling; Mus; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Pre-Clinical Model; Principal Investigator; Proteins; Reporting; Research Design; Resistance; Role; Safety; Serum; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Small Interfering RNA; Staging; Stimulus; Stress; Testing; Therapeutic; Tissues; Toxic effect; Transactivation; Translation Process; Xenograft procedure; base; chemotherapy; comparative; data mining; deprivation; design; docetaxel; feeding; hormone refractory prostate cancer; improved; inhibitor/antagonist; interest; loss of function; men; neoplastic cell; new therapeutic target; overexpression; phase 2 study; prevent; programs; protein profiling; research study; response; serum PSA; therapeutic target; tool; transcription factor; tumor progression

This renewal application will build on our previous studies, in which we established a roles heat shock protein (Hsp) 27 as a stress-induced cytoprotective chaperone that increases after hormone- and chemo- therapy to inhibit treatment-induced cell death. We will explore the hypothesis that Hsp27 is a therapeutic "hyper-node", a target situated as a 'Hub" at the center of many pathways regulating the response to cell stress and therapeutic stimuli. Hsp27 forms oligomers during cell stress to prevent aggregation, or becomes phosphorylated to chaperone and regulate activity or degradation of many varied client proteins, including the transcriptional activity of stat-3 and AR. Aim 1will elucidate pathways by which Hsp27 regulates CaP cell survival, using bioprofiling and directed functional approaches. Gene and antibody expression profiles of Hsp27 overexpression vs knockdown, coupled to ingenuity pathway analysis, will identify gene networks affected by Hsp27. In parallel, Aim 2 will focus on roles of Hsp27 in 3 pathways linked to HRPC and therapeutic resistance, and specifically test a) whether ligand-independent (androgen depleted) AR activity associated with Al progression is modulated by interactions between IL-6signal transduction, ligand- depleted AR transactivation, and increased Hsp27 activity; b) effects of Hsp27-induced PEA-15 phosphorylation on cell proliferation (by promoting ERK/MAPK activation) and inhibition of Fas mediated cell death, and c) whether treatment induced stress up-regulates the unfolded protein response (DPR) in CaP, and the role of Hsp27 is a downstream effector in endoplasmic reticular (ER) stress. Aim 3 will evaluate the safety and activity of an Hsp27 antisense inhibitor (OGX-427) in a Phase I/II study in men with mHRPC. The phase I portion will define the pharmacokinetic and toxicity profile of OGX-427 and determine the recommended phase II dose of OGX-427 given as a 2-hour IV infusion once weekly. The phase II portion of this study will then evaluate the anti-cancer activity of OGX-427, assessed primarily by PSA "response", in part as a pharmacodynamic surrogate of AR inhibition. Correlative studies are also incorporated to evaluate the biologic effectiveness of OGX-427 by analysis of bone marrow aspirates and tissue for Hsp27 and AR protein levels. Collectively, these studies will improve our understanding of role of Hsp27 in adaptive cell survival, treatment resistance, and most importantly, as a new therapeutic target in mHRPC.

该更新应用程序将建立在我们之前的研究的基础上，在该研究中我们建立了热休克角色 蛋白 (Hsp) 27 作为应激诱导的细胞保护伴侣，在激素和化疗后增加 抑制治疗引起的细胞死亡的疗法。我们将探讨 Hsp27 是一种治疗药物的假设 “超级节点”，一个位于调节细胞反应的许多途径中心的“枢纽”的目标 压力和治疗刺激。 Hsp27 在细胞应激过程中形成寡聚体以防止聚集，或者变成 磷酸化为伴侣并调节许多不同客户蛋白的活性或降解，包括 stat-3 和 AR 的转录活性。目标 1 将阐明 Hsp27 调节 CaP 细胞的途径 生存，使用生物分析和定向功能方法。基因和抗体表达谱 Hsp27 过表达与敲低，结合独创性途径分析，将识别基因网络 受 Hsp27 影响。与此同时，目标 2 将重点关注 Hsp27 在与 HRPC 相关的 3 条通路中的作用，以及 治疗耐药性，并特别测试 a) 是否具有配体独立性（雄激素耗尽）AR 活性 与 Al 进展相关的细胞因子通过 IL-6 信号转导、配体- 耗尽 AR 反式激活，并增加 Hsp27 活性； b) Hsp27 诱导的 PEA-15 的影响 磷酸化对细胞增殖的影响（通过促进 ERK/MAPK 激活）和抑制 Fas 介导的细胞 死亡，以及 c) 治疗引起的应激是否上调 CaP 中的未折叠蛋白反应 (DPR)， Hsp27 是内质网 (ER) 应激中的下游效应子。目标 3 将评估 Hsp27 反义抑制剂 (OGX-427) 在 mHRPC 男性 I/II 期研究中的安全性和活性。这 第一阶段部分将定义 OGX-427 的药代动力学和毒性特征，并确定 建议每周一次 2 小时静脉输注 OGX-427 的 II 期剂量。二期部分 然后，这项研究将评估 OGX-427 的抗癌活性，主要通过 PSA“反应”进行评估， 部分作为 AR 抑制的药效学替代物。还纳入了相关研究来评估 通过分析骨髓抽吸物和组织中的 Hsp27 和 AR 来确定 OGX-427 的生物学有效性 蛋白质水平。总的来说，这些研究将提高我们对 Hsp27 在适应性细胞中作用的理解 生存率、治疗耐药性，最重要的是，作为 mHRPC 的新治疗靶点。