Inducible systems for studying liver tumor mainenance in vivo

用于研究肝脏肿瘤体内维持的诱导系统

• 批准号: 9457376
• 负责人: Xin Chen
• 金额: $ 7.93万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9457376
• 关键词: Ablation; Address; BAY 54-9085; Cancer Etiology; Cessation of life; Clinical Trials; Complex; Critical Pathways; Data; Development; Disease; EIF4EBP1 gene; Event; FRAP1 gene; Gene Expression; Genes; Genetic; Genetic Engineering; Goals; Hepatocarcinogenesis; Injections; Lead; Life; Liver; Liver neoplasms; MAP Kinase Gene; MYC gene; Maintenance; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Modeling; Molecular; Molecular Genetics; Mus; Oncogenes; Pathogenesis; Pathway interactions; Patients; Primary carcinoma of the liver cells; Raptors; Research; Research Project Grants; Role; SDZ RAD; Signal Pathway; Signal Transduction; Sirolimus; Sleeping Beauty; Solid; Study models; System; Technology; Testing; Transfection; beta catenin; c-myc Genes; effective therapy; experimental study; flexibility; in vivo; inhibitor/antagonist; insight; mouse model; neoplastic cell; novel; novel strategies; novel therapeutics; overexpression; targeted treatment; tumor; tumor growth; tumor initiation; tumor progression

Abstract Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. However, molecular genetics underlying HCC development remain to be poorly understood. Treatment options for HCC are very limited and in general ineffective. There is only a single option for treatment of advanced HCC (Sorafenib) which prolongs life by an average of just three months! Consequently, there is a pressing unmet need for new insights on HCC that will lead to new therapies. The growing understanding of molecular pathogenesis of HCC, on the other hand, does open the door for novel strategy of targeted therapy. Hydrodynamic transfection combines hydrodynamic injection together with sleeping beauty mediated somatic integration for long term gene expression. Because of its flexibility and high efficiency, it has now becoming increasingly popular to be used to generate murine models for studying hepatocarcinogenesis. However, so far few inducible systems have been established for this technology. Amplification and overexpression of c-Myc oncogene is one of the most frequently observed genetic events during HCC pathogenesis; and c-Myc is considered to be an important driver oncogene for HCC. Indeed overexpression of c-Myc in mouse liver promotes the formation of poorly differentiated HCC. Recently, we discovered that ablation of Raptor, the unique component of mTORC1, significantly suppressed c-Myc driven HCC development in vivo. However, it is not clear whether mTORC1 is required for c-Myc HCC maintenance and whether inhibition of mTORC1 leads to HCC regression. In this application, we hypothesize that mTORC1 is required for c-Myc maintenance; and deleting Raptor after tumor formation will lead to tumor regression. In this R03 small application, we will establish an efficient inducible Cre system for hydrodynamic transfection (Aim 1). We will then apply the technology to delete Raptor in c-Myc induced HCC tumors in vivo with the goal to study whether mTORC1 complex is required for maintaining c-Myc HCC (Aim 2). Altogether, this is a self-contained research projects which fits well with the description and scope of a R03 small research project. It assists to develop a powerful research technology which can be used to characterize the requirement of a gene or pathway for HCC maintenance. The results from such studies are critical for establishing the gene or pathway for the treatment of HCC.

摘要