Drug Targets of Heat Shock Response

描述（由申请人提供）：细胞应激诱导的热休克反应（HSR）是在广泛的肿瘤中引起的常见保护机制。这种反应与不良预后和对治疗的抵抗密切相关。这项研究的第一阶段旨在确定参与HSR的药物靶点。这些预期抑制HSR的潜在药物可以与已知的细胞应激激活剂（例如热休克、硼替佐米和格尔德霉素）组合使用，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通路调控的原型数据库。 本研究的第二阶段提出了深入表征参与HSR/PTS途径的药物靶点，并开发了用于化合物库高通量筛选（HTS）的报告细胞系。鉴于我们与Roswell Park癌症中心提供的基于细胞的药物筛选设施的独特接口，我们希望开发一种潜在药物的管道，将途径知识快速转化为有效的药物鉴定策略。 在完成拟议的研究时，我们预计我们将产生一类新的抗肿瘤药物，这些药物没有先前在文献中描述或应用于临床试验的等效特性。我们建议将这些药物与已知通过抑制基础热休克机制激活HSR的药物（如硼替佐米和格尔德霉素）联合使用，或与热疗法联合使用。我们的初步研究表明，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，以建立新的方法，通过分离阻断肿瘤热休克反应的化合物来发现抗癌疗法。药物靶点将通过RNAi技术进行鉴定，从而允许开发RNAi文库产品并生成细胞系、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.