Studying the role of eIF4A in Pancreatic Cancer

项目总结 胰腺导管腺癌(PDA)在很大程度上仍然无法治愈，最近的研究表明， PDA细胞的代谢途径发生了深刻的重新连接。尽管如此，这种新陈代谢的重新连接也可能 产生可用于PDA治疗的负债。使用基因工程小鼠模型和 胰腺导管器质，我们先前已经证明PDA细胞依赖于KRAS介导的 蛋白质合成增加。当几条关键的致癌信号通路汇聚在真核生物上时 翻译起始因子4F(EIF4F)，我们最近研究了其相关RNA的抑制物(CR-31) 解旋酶(EIF4A)影响PDA细胞的活性。值得注意的是，CR-31损害了编码mRNA的翻译 在PDA的细胞中，酶选择性地参与各种代谢途径，而不是正常的导管类器官。 此外，虽然吉西他滨是目前唯一一种治疗PDA的单一疗法，但不能延长PDA的存活期。 在荷瘤小鼠体内，我们观察到单独使用CR-31抑制了PDA肿瘤的生长。因此，我们假设 EIF4A是胰腺癌转化的关键调节因子，具有作为治疗靶点的独特潜力 掌上电脑。为了实现eIF4A抑制在临床上的潜力，我们建议定义eIF4A抑制的机制 胰腺癌细胞中eIF4A依赖的转录特异性翻译(Aim 1)，确定翻译 促进PDA的eIF4A靶点(目标2)，并确定eIF4A抑制诱导的适应可以协同 旨在更有效地治疗这种致命的恶性肿瘤(目标3)。这个项目建立在我们在PDA方面的专业知识基础上 生物学、器官培养、rna基因组分析，以及获取患者来源的样本以评估 临床相关性。除了阐明基本机制外，拟议中的研究还将测试几种新颖的 掌上电脑的治疗选择。

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.