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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.

总结