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

基本信息

批准号：
8330638
负责人：
MARTIN GLEAVE
金额：
$ 25.91万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8330638
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 MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of prostate Mediating Mediator of activation protein Molecular Chaperones Molecular Profiling Mus Pacific Northwest 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 man 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

项目摘要

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 个途径中的作用，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IL-6信号转导、配体-之间的相互作用调节耗尽 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 I 期部分将定义 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。