eIF2a phosphorylation as a novel druggable target in CRPC

描述（由申请人提供）：本研究项目的主要目标是确定新的“可药物途径”来对抗去势抵抗性前列腺癌（CRPC），这是一种治疗抵抗性的致命形式的前列腺癌。主要方法是严格审查实验室使用基因功能丧失筛选涉及CRPC的新生化途径，这使得能够提前发现导致治疗（即阉割）抗性的变化。除了已知的肿瘤抑制途径——SRC抑制激酶CSK和GSK3ß，这两种途径在组织培养研究、动物模型和人类前列腺癌组织样本中得到了进一步的验证，筛选还涉及到其他几种途径，即影响NF-κ b和真核翻译起始因子2α (eIF2α)的途径。在目前的探索性R21项目中，这些新涉及的途径之一将在两个具体目标中进行剖析：(i)在组织培养模型中，eIF2α磷酸化缺失对雄激素剥夺诱导的生长停滞的贡献将被确定。(2)。这些途径的功能作用将在小鼠模型（异种移植物，转基因）中进行检查。这些新的靶标途径不仅将在功能上得到验证，而且它们的活性也将用现有的类药物化合物进行修饰，以提供概念证明，证明它们适用于药物治疗（即药物治疗）。“制药”)。值得注意的是，这种方法在以往的SRC/CSK研究中取得了巨大的成功。在两年内，计划中的研究预计将为推进现有药物样化合物进入临床开发/应用或启动能够调节途径的小分子筛选提供强有力的理由，这些研究将导致CRPC的治疗耐药性。

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.