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: 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
• 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

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.

这种更新应用将建立在我们以前的研究，其中我们建立了一个角色热休克 蛋白（热休克蛋白）27作为应激诱导的细胞保护分子伴侣，在激素和化疗后增加， 治疗以抑制治疗诱导的细胞死亡。我们将探讨Hsp 27是一种治疗性的假设， “超节点”，一个位于许多调节细胞应答的途径中心的“枢纽”靶点。 压力和治疗刺激。Hsp 27在细胞应激期间形成寡聚体以防止聚集，或成为 磷酸化为伴侣蛋白并调节许多不同的客户蛋白的活性或降解，包括 stat-3和AR的转录活性。目的1阐明热休克蛋白27对CaP细胞的调控途径 生存，使用生物谱分析和定向功能方法。基因和抗体表达谱 Hsp 27过表达与敲低，加上独创性途径分析，将确定基因网络 受HSP 27影响。同时，目标2将重点关注Hsp 27在与HRPC相关的3条途径中的作用， a）配体非依赖性（雄激素耗尽）AR活性是否 与Al进展相关的是通过IL-6信号转导、配体- 耗尽AR反式激活和增加Hsp 27活性; B）Hsp 27诱导的PEA-15的作用 磷酸化对细胞增殖的影响（通过促进ERK/MAPK活化）和抑制Fas介导的细胞增殖 死亡，和c）处理诱导的应激是否上调CaP中的未折叠蛋白反应（DPR）， Hsp 27是内质网应激的下游效应子。目标3将评估 Hsp 27反义抑制剂（OGX-427）在mHRPC患者中的I/II期研究中的安全性和活性。的 I期部分将确定OGX-427的药代动力学和毒性特征，并确定OGX-427的毒性。 推荐的II期剂量的OGX-427作为2小时IV输注每周一次给予。的II期部分 然后，本研究将评估OGX-427的抗癌活性，主要通过PSA“反应”评估， 部分作为AR抑制的药效学替代物。还结合相关研究进行评估 通过分析骨髓抽吸物和组织中的Hsp 27和AR，确定OGX-427的生物学有效性 蛋白质水平总之，这些研究将提高我们对热休克蛋白27在适应性细胞中作用的理解， 存活率、治疗耐药性，最重要的是作为mHRPC的新治疗靶点。