Drug Targets of Heat Shock Response

描述(申请人提供)：由细胞应激诱导的热休克反应(HSR)是一种常见的保护机制，在广泛的肿瘤中诱导。这种反应与预后不良和对治疗的抵抗密切相关。这项拟议研究的第一阶段旨在确定高铁涉及的药物靶标。这些有望抑制HSR的潜在药物可能与已知的细胞应激激活剂，如热休克、Bortezomib和格尔达那霉素联合使用，以改善癌症的治疗。此外，拟议研究的第一阶段的完成将导致在不同肿瘤来源的广泛细胞系中产生HSR途径调控的原型数据库。 这项研究的第二阶段建议深入表征HSR/PTS途径中涉及的药物靶点，并开发用于高通量筛选(HTS)化合物文库的报告细胞系。鉴于我们与罗斯威尔公园癌症中心现有的基于细胞的药物筛选设施的独特接口，我们希望开发一条潜在药物的管道，将途径知识快速转化为有效的药物识别策略。 在拟议的研究完成后，我们预计我们将产生一类新的抗肿瘤药物，这些药物没有文献中描述的或在临床试验中应用过的同等性质。我们建议这些药物与已知通过抑制基础热休克机制而激活HSR的药物(如Bortezomib和Geldanamicin)联合使用，或与热疗联合使用。我们的初步研究支持这些药物在诱导肿瘤细胞死亡方面具有非常强的协同作用。 公共卫生相关性：该项目的目标是确定热休克反应途径中的药物靶点，以建立通过分离阻断肿瘤中热休克反应的化合物来发现抗癌治疗的新方法。药物靶点将通过RNAi技术确定，从而允许开发RNAi库产品和生成细胞系、基因和分子途径的数据库。

DESCRIPTION (provided by applicant): The heat shock response (HSR) induced by cell stress is a common protection mechanism elicited in a wide range of tumors. This response is closely associated with a poor prognosis and resistance to therapy. Phase I of this proposed research aims to identify drug targets involved in the HSR. These potential drugs, which are expected to inhibit the HSR, may be used in combination with known activators of cell stress, such as heat shock, Bortezomib and Geldanamycin, for improved treatment of cancers. In addition, completion of Phase I of the proposed research will result in generation of a prototype database of HSR pathway regulation in a wide range of cell lines of diverse tumor origin. Phase II of this research proposes in-depth characterization of drug targets involved in the HSR/PTS pathway and development of the reporter cell lines for high throughput screening (HTS) of a chemical compound library. Given our unique interface with cellbased drug screening facilities available at Roswell Park Cancer Center, we expect to develop a pipeline of potential drugs with fast conversion of pathway knowledge into efficient strategies of drug identification. At completion of the proposed studies, we anticipate that we will have generated a novel class of anti-tumor drugs with no equivalent properties previously described in the literature or applied in clinical trials. We propose that these drugs be used in combination with drugs known to activate the HSR through inhibition of basal heat shock machinery, such as Bortezomib and Geldanamicin, or in combination with heat therapy. Our preliminary studies argue in favor of a very strong synergistic effect of these drugs in the induction of tumor cell death. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify drug targets within the heat shock response pathway for establishment of novel approaches to discover anti-cancer therapies through isolation of chemical compounds blocking heat shock response in tumors. Drug targets will be identified through RNAi technology, allowing for development of RNAi library products and generation of databases of cell lines, genes, and molecular pathways.