eIF2a phosphorylation as a novel druggable target in CRPC

eIF2a 磷酸化作为 CRPC 的新型药物靶点

基本信息

批准号：
8805370
负责人：
RANDAL J. KAUFMAN
金额：
$ 25.45万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-05 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8805370
关键词：
Address Androgen Receptor Androgens Animal Model Biochemical Pathway Biological Castration Cell Aging Cell Cycle Arrest Cell Death Cells Cellular biology Cessation of life Chemicals Clinical Clinical Management Complement Development Disease Down-Regulation Drug Targeting Elements Etiology Eukaryotic Initiation Factors Genetic Goals Growth Human In Vitro Investigation Knock-out LAPC4 LNCaP Life Ligands Link Malignant neoplasm of prostate Modeling Molecular Mus Mutation Pathway interactions Pharmaceutical Preparations Pharmacotherapy Phenotype Phosphorylation Phosphotransferases Process Prostate Prostate Cancer therapy Proteins Research Resistance Role Signal Transduction Small Interfering RNA Testing Therapeutic Tissue Sample Transgenic Organisms Ursidae Family Xenograft Model Xenograft procedure castration resistant prostate cancer combat deprivation drug development in vivo innovation knock-down loss of function meetings member mouse model novel novel therapeutics programs prostate cancer cell public health relevance research study response senescence small molecule success therapy resistant tissue culture tumor tumor growth

Address Androgen Receptor Androgens Animal Model Biochemical Pathway Biological Castration Cell Aging Cell Cycle Arrest Cell Death Cells Cellular biology Cessation of life Chemicals Clinical Clinical Management Complement Development Disease Down-Regulation Drug Targeting Elements Etiology Eukaryotic Initiation Factors Genetic Goals Growth Human In Vitro Investigation Knock-out LAPC4 LNCaP Life Ligands Link Malignant neoplasm of prostate Modeling Molecular Mus Mutation Pathway interactions Pharmaceutical Preparations Pharmacotherapy Phenotype Phosphorylation Phosphotransferases Process Prostate Prostate Cancer therapy Proteins Research Resistance Role Signal Transduction Small Interfering RNA Testing Therapeutic Tissue Sample Transgenic Organisms Ursidae Family Xenograft Model Xenograft procedure castration resistant prostate cancer combat deprivation drug development in vivo innovation knock-down loss of function meetings member mouse model novel novel therapeutics programs prostate cancer cell public health relevance research study response senescence small molecule success therapy resistant tissue culture tumor tumor growth

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项目摘要

DESCRIPTION (provided by applicant): The main goal of this research program is to identify novel "druggable pathways" to combat castration-resistant prostate cancer (CRPC), the therapy-resistant, lethal form of prostate cancer. The principal approach is to rigorously scrutinize novel biochemical pathways the lab has implicated in CRPC using a genetic loss-of-function screen, which enabled the upfront discovery of alterations that cause therapy (i.e. castration) resistance. In addition to known tumor suppressive pathways - SRC inhibitory kinase CSK and GSK3ß, which were further validated in tissue culture studies, animal models, and human prostate cancer tissue samples, the screen implicated several additional pathways, namely those impinging on NF-κB and the eukaryotic translation initiation factor 2α (eIF2α). In the present exploratory R21 project, one of these newly implicated pathways will be dissected in two specific aims: (i.) In tissue culture models, the contributions of deficiency in eIF2α phosphorylation to androgen deprivation-induced growth arrest will be determined. (ii.) The functional role of these pathways will be examined in mouse models (xenografts, transgenics). Not only will these new target pathways be validated functionally, but their activity will also be modified with existing drug-like compounds in order to provide proof-of-concept that they are amenable to pharmacotherapy (i.e. "druggable"). Notably, this approach has met with great success in the previous studies on SRC/CSK. Within two years, the planned investigations are expected to provide a strong rationale for either advancing an existing drug-like compound into clinical development/application or for initiating a screen for small molecules able to modulate the pathways these studies will causally implicate in the therapy resistance of CRPC.

描述（由适用提供）：该研究计划的主要目标是确定新颖的“可药途径”来打击耐castration-耐castration的前列腺癌（CRPC），这是耐药的，致命的前列腺癌。主要方法是严格仔细检查新型的生化途径该实验室已在CRPC中使用遗传功能丧失屏幕实施，这使得能够预先发现引起治疗（即cast割）耐药性的变化。除了已知的肿瘤抑制途径-SRC抑制性激酶CSK和GSK3ß，在组织培养研究，动物模型和人类前列腺癌组织样品中得到了进一步验证，该屏幕还暗示了几种其他途径，即在NF -κB和真核转化启动因子2α（EIF2α）上引起的途径。在当前的探索性R21项目中，将在两个具体目的中阐述这些新实施的途径之一：（i。）在组织培养模型中，将确定EIF2α磷酸化对雄激素剥夺引起的生长滞留的缺乏的贡献。（ii。）这些途径的功能作用将在小鼠模型（异种移植物，转化学）中进行检查。这些新的目标途径不仅可以通过功能验证，而且它们的活性也将通过现有的类似药物的化合物来修饰，以便提供概念验看，表明它们可以适合药物治疗（即“可药用”）。值得注意的是，这种方法在先前关于SRC/CSK的研究中取得了巨大成功。在两年内，预计计划的研究将为将现有药物样化合物推进临床开发/应用或启动能够调节这些研究的小分子的筛查提供有力的基本原理。