Characterization and Targeting of the Cytoprotective Chaperone, HSP27

此续订申请将建立在我们之前的研究基础上，在这些研究中，我们建立了热冲击角色 蛋白(HSP)27作为应激诱导的细胞保护性伴侣，在激素和化疗后增加- 抑制治疗诱导的细胞死亡的治疗。我们将探讨Hsp27是一种治疗药物的假设。 “超级节点”，一个位于许多调节细胞反应的通路中心的“中心”。 压力和治疗性刺激。Hsp27在细胞应激期间形成寡聚体以防止聚集，或者成为 被磷酸化为伴侣，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调控帽细胞的途径 生存，使用生物剖析和定向功能方法。鸡传染性支气管炎基因和抗体表达谱 Hsp27过度表达与基因敲除相比，结合独创性途径分析，将识别基因网络 受Hsp27感染。同时，目标2将侧重于Hsp27在与hrpc和hrpc相关的3条途径中的作用。 治疗耐药性，并具体测试a)是否具有配体非依赖(雄激素耗竭)的AR活性 与阿尔茨海默病的进展相关的是通过IL-6信号转导、配体- 抑制AR反式激活，增加Hsp27活性；b)Hsp27诱导PEA-15的作用 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)治疗诱导的应激是否上调帽子中的未折叠蛋白反应(DPR)， Hsp27是内质网应激的下游效应因子。AIM 3将评估 Hsp27反义抑制剂(OGX-427)在男性mHRPC患者I/II期研究中的安全性和活性。这个 第一阶段将确定OGX-427的药代动力学和毒性分布，并确定 推荐的第二阶段剂量的OGX-427，每周一次，静脉滴注2小时。第二期工程 这项研究将评估OGX-427的抗癌活性，主要通过PSA“反应”来评估，在 部分作为AR抑制的药效学替代物。相关研究也被纳入评估中。 OGX-427骨髓抽提物和组织中Hsp27和AR的生物学效应 蛋白质水平。总之，这些研究将提高我们对Hsp27在适应性细胞中的作用的理解 生存、治疗耐药性，最重要的是，作为mHRPC的新治疗靶点。

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.