eIF2a phosphorylation as a novel druggable target in CRPC

描述（由申请人提供）：本研究计划的主要目标是确定新的“药物途径”，以打击去势抵抗性前列腺癌（CRPC），治疗抵抗性，致命的前列腺癌形式。主要方法是严格审查实验室使用遗传功能丧失筛选与CRPC有关的新型生化途径，这使得能够预先发现导致治疗（即去势）抗性的改变。除了已知的肿瘤抑制途径- SRC抑制性激酶CSK和GSK 3 β，这些途径在组织培养研究、动物模型和人前列腺癌组织样本中得到了进一步验证，该筛选还涉及几种其他途径，即影响NF-κB和真核翻译起始因子2α（eIF 2 α）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解剖：（i.）在组织培养模型中，将确定eIF 2 α磷酸化缺陷对雄激素剥夺诱导的生长停滞的贡献。（二）申请人;将在小鼠模型（异种移植物、转基因）中检查这些途径的功能作用。这些新的靶向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药物样化合物进行修饰，以提供概念验证，证明它们适合药物治疗（即“可药物化”）。值得注意的是，这种方法在以前的SRC/CSK研究中取得了巨大成功。在两年内，计划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这些研究将因果地影响CRPC的治疗抗性的途径的小分子的筛选提供强有力的理由。

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.