Studying the role of eIF4A in Pancreatic Cancer

研究 eIF4A 在胰腺癌中的作用

基本信息

批准号：
10529955
负责人：
Iok In Christine Chio
金额：
$ 50.76万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10529955
关键词：
5&apos Untranslated Regions Affect Biological Biological Assay Biology CRISPR/Cas technology Cell Death Cell Survival Cells Clinical Combined Modality Therapy Data Dependence Development Doxycycline Duct (organ) structure Ductal Epithelial Cell Enzymes Ethers Etiology Eukaryotic Initiation Factors Genetic Translation Genetically Engineered Mouse Glucose Transporter Goals Impairment Iron KRAS2 gene Knock-out Link Malignant Neoplasms Malignant neoplasm of pancreas Mediating Messenger RNA Metabolic Metabolic Pathway Modeling Mouse Strains Mus Mutation Oncogenic Organoids Oxides Pancreatic Ductal Adenocarcinoma Pancreatic duct Patients Phospholipids Polyribosomes Polyunsaturated Fatty Acids Protein Biosynthesis Proteins Quantitative Reverse Transcriptase PCR RNA Caps RNA Folding RNA Helicase Regulation Reporter Resistance Role Signal Pathway Specimen Testing Therapeutic Transcript Transcription Initiation Transcription Initiation Site Translations Up-Regulation Work base biochemical tools clinically relevant dimethyl sulfate gemcitabine genomic RNA genomic tools glucose metabolism glucose uptake improved in vivo inhibitor insight novel novel therapeutics pancreatic cancer cells pancreatic ductal adenocarcinoma cell pancreatic tumorigenesis patient response predictive marker programs resistance mechanism small hairpin RNA synergism therapeutic target translatome transplant model tumor growth

项目摘要

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.

项目摘要胰腺导管腺癌（PDA）仍然无法治愈，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，这种代谢重新布线也可能可以利用用于PDA治疗的责任。使用遗传设计的小鼠模型和胰管导管器官，我们先前表明PDA细胞取决于KRAS介导的蛋白质合成的增加。随着几个关键的致癌信号通路在真核上汇聚翻译起始因子4F（EIF4F），我们最近检查了其相关RNA的抑制剂（CR-31）是否是否解旋酶（EIF4A）影响PDA细胞的生存能力。令人惊讶的是，CR-31损害了mRNA编码的翻译在PDA细胞中选择性地参与各种代谢途径的酶，但不是正常的导管器官。此外，虽然吉西他滨是PDA现有的唯一单药治疗，但并没有扩展PDA-的存活率轴承小鼠，我们观察到CR-31仅抑制了体内PDA肿瘤的生长。因此，我们假设 EIF4A是胰腺癌翻译的关键调节剂，具有独特的潜力作为治疗靶标 PDA。为了在临床环境中实现EIF4A抑制的潜力，我们建议定义胰腺癌细胞中依赖EIF4A的依赖性转录特异性翻译（AIM 1），确定翻译促进PDA的EIF4A靶标（AIM 2），并确定EIF4A抑制作用引起的适应针对更有效地治疗这种致命的恶性肿瘤（AIM 3）。该项目以我们在PDA的专业知识为基础生物学，器官培养，RNA基因组分析以及对患者衍生标本的访问评估临床相关性。除了阐明基本机制外，拟议的研究还将测试几种新型 PDA的治疗选择。