Studying the role of eIF4A in Pancreatic Cancer

项目摘要 胰腺导管腺癌（PDA）在很大程度上仍然是不可治愈的，最近的研究表明， PDA细胞的代谢途径被深刻地重新连接。尽管如此，这种代谢重组也可能 产生的负债，可用于PDA治疗。使用基因工程小鼠模型， 胰腺导管类器官，我们以前表明PDA细胞依赖于KRAS介导的 蛋白质合成增加。当几个关键的致癌信号通路在真核细胞上汇合时， 翻译起始因子4F（eIF 4F），我们最近研究了其相关RNA的抑制剂（CR-31） 解旋酶（eIF 4A）影响PDA细胞的活力。引人注目的是，CR-31损害了编码 PDA细胞中选择性参与各种代谢途径的酶，而不是正常的导管类器官。 此外，虽然吉西他滨是目前唯一的PDA单药治疗，但不能延长PDA的生存期， 在荷瘤小鼠中，我们观察到单独的CR-31抑制体内PDA肿瘤生长。因此，我们假设， eIF 4A是胰腺癌翻译的关键调节因子，具有作为治疗靶点的独特潜力。 掌上电脑。为了实现eIF 4A抑制在临床环境中的潜力，我们建议定义以下机制： 胰腺癌细胞中eIF 4A依赖性转录特异性翻译（Aim 1）， eIF 4A促进PDA的靶点（目的2），并鉴定由eIF 4A抑制诱导的适应， 目的是更有效地治疗这种致命的恶性肿瘤（目的3）。这个项目建立在我们在PDA的专业知识 生物学，类器官培养，RNA基因组分析，以及获得患者来源的标本，以评估 临床相关性除了阐明基本机制外，拟议的研究还将测试几种新的 PDA的治疗选择

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) remains largely incurable and recent studies have shown that the metabolic pathways of PDA cells are profoundly rewired. Nonetheless, this metabolic rewiring may also engender liabilities that can be exploited for PDA treatment. Using genetically-engineered mouse models and pancreatic ductal organoids, we previously showed that PDA cells are dependent upon KRAS-mediated increases in protein synthesis. As several key oncogenic signaling pathways converge on the eukaryotic translation initiation factor 4F (eIF4F), we recently examined whether an inhibitor (CR-31) of its associated RNA helicase (eIF4A) affects the viability of PDA cells. Strikingly, CR-31 impaired the translation of mRNAs encoding enzymes involved in various metabolic pathways selectively in cells of PDA, but not normal, ductal organoids. Moreover, while gemcitabine, the only existing monotherapy for PDA, does not extend the survival of PDA- bearing mice, we observed that CR-31 alone suppressed PDA tumor growth in vivo. Thus, we hypothesize that eIF4A is a key regulator of pancreatic cancer translation with unique potential as a therapeutic target against PDA. To realize the potential of eIF4A inhibition in the clinical setting, we propose to define the mechanism of eIF4A-dependent transcript-specific translation in pancreatic cancer cells (Aim 1), determine the translational targets of eIF4A that promote PDA (Aim 2), and identify adaptations induced by eIF4A inhibition that can be co- targeted to more effectively treat this lethal malignancy (Aim 3). This project builds on our expertise in PDA biology, organoid culture, RNA genomic analysis, as well as access to patient-derived specimens to evaluate clinical relevance. In addition to illuminating basic mechanisms, the proposed studies will test several novel treatment options for PDA.