Translation addiction and targeting in colon cancer

结肠癌的翻译成瘾和靶向治疗

基本信息

批准号：
10317055
负责人：
Jian Yu
金额：
$ 45.98万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317055
关键词：
APC mutation Acute Affect BRAF gene Cancer Biology Cancer Cell Growth Cancer Etiology Cell Death Cell Line Cell Proliferation Cell Survival Cell model Cessation of life Clinical Colon Carcinoma Colorectal Cancer Complex Data Dependence Development Eukaryotic Initiation Factor-4F Evolution FRAP1 gene Feedback Genetic Transcription Genetic Translation Glutamine Human Hyperactivity Individual Intestinal Polyposis KRAS2 gene Knock-in Lead Malignant Neoplasms Mediating Metabolic Metabolic stress Metabolism Modeling Mus Mutation Normal tissue morphology Oncogenic PI3K/AKT Pathway interactions Pharmacology Phosphorylation Phosphotransferases Proteins Publications RNA Cap-Binding Proteins Ras/Raf Resistance Role Sampling Signal Transduction Specificity Stress Systems Biology TNFRSF10B gene Testing Toxic effect Transcript Translating Translations WNT Signaling Pathway Work Xenograft procedure addiction arm biological adaptation to stress c-myc Genes cancer cell cancer initiation cancer therapy colon cancer treatment effective therapy endoplasmic reticulum stress improved in vivo inhibitor innovation mouse model multicatalytic endopeptidase complex mutant novel novel drug combination patient derived xenograft model potential biomarker programs public health relevance success targeted treatment tool translational approach tumor progression tumorigenesis

项目摘要

Summary Colorectal cancer (CRC) represents a leading cause of cancer death in the US and worldwide, and its development is driven by mutational activation of Wnt, RAS/RAF/ERK and PI3K/AKT/mTOR signaling. However, targeting individual driver in CRC has limited success. Wnt, mTOR and ERK signaling converges to deregulate eIF4F and lead to translate key oncogenic targets including c-Myc. Interestingly, phosphorylated eIF4E (S209, or p-eIF4E) is dispensable for development or global translation, but required for transformation and optimal tumorigenesis in some models. The underlying causes and significance of elevated p-eIF4E in human cancer and oncogenic translation remains largely unknown. Our novel preliminary data and recent publications supports a critical role of p-eIF4E in human and mouse colon cancer development, and in regulating colon cancer proliferation via ATF4-mediated metabolic and stress adaptation. Pharmacological targeting of eIF4E/4F induces endoplasmic reticulum stress and CRC cell death in culture and in vivo. The central hypothesis of the project is that phosphorylated eIF4E drives colon cancer initiation and progression through ATF4-dependent metabolic and stress reprogramming and serves as an actionable and druggable vulnerability. We will test this hypothesis in three specific Aims. SA1. Define the role of eiF4E phosphorylation in colon cancer development. SA2. Elucidate the mechanisms of p-eIF4E-dependent oncogenesis in colon cancer. SA3. Target eIF4F/4E in colon cancer therapy. The proposed work will develop and employ innovative tools, including phosphorylation defective eIF4E cancer cells and mice, clinical samples, and highly mechanistic and comprehensive approaches to define the role of p-eIF4E in colon cancer biology and therapy. If successful, our work will provide a better understanding of oncogenic translation in protective stress and metabolic adaptation, as well as strategies to target this addiction for therapy. These findings will likely have important implications in treating other cancers with hyperactive Wnt and RAS/RAF for which no effective therapy currently exists.

概括结直肠癌（CRC）代表了美国和全球癌症死亡的主要原因，它开发是由Wnt，RAS/RAF/ERK和PI3K/AKT/MTOR信号传导的突变激活驱动的。然而，针对CRC中的个别驾驶员的成功有限。 Wnt，MTOR和ERK信号转换为放松管制 EIF4F并导致转化包括C-Myc在内的关键致癌靶标。有趣的是，磷酸化的EIF4E（s209，或p-eif4e）对于开发或全球翻译是可置的，但需要转换和最佳在某些模型中的肿瘤发生。 P-EIF4E在人类癌症中的基本原因和意义并且致癌翻译在很大程度上仍然未知。我们新颖的初步数据和最新出版物支持 P-EIF4E在人和小鼠结肠癌发展中的关键作用，并在调节结肠癌中通过ATF4介导的代谢和应力适应的增殖。 EIF4E/4F的药理靶向在培养和体内诱导内质网应激和CRC细胞死亡。中心假设项目是，磷酸化的EIF4E通过ATF4依赖性驱动结肠癌的启动和进展代谢和压力重编程，并作为可起作用的可毒品脆弱性。我们将测试这个三个特定目标的假设。 SA1。定义EIF4E磷酸化在结肠癌发展中的作用。 SA2。阐明了结肠癌中P-EIF4E依赖性肿瘤发生的机制。 SA3。目标EIF4F/4E英寸结肠癌疗法。拟议的工作将开发和采用创新工具，包括磷酸化 EIF4E癌细胞和小鼠，临床样本以及高度机械和全面的方法有缺陷定义P-EIF4E在结肠癌生物学和治疗中的作用。如果成功，我们的工作将提供更好的了解保护应力和代谢适应中的致癌翻译，以及以这种成瘾为目标进行治疗。这些发现可能对治疗其他癌症具有重要意义对于目前尚无有效疗法的多动症Wnt和RAS/RAF。