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 肝细胞癌（HCC）是第五大常见癌症，也是癌症死亡的第三大原因 国际吧然而，HCC发生的分子遗传学基础仍然知之甚少。 HCC的治疗选择非常有限，并且通常无效。只有一个选择， 治疗晚期肝癌（索拉非尼），平均寿命仅延长三个月！因此，委员会认为， 对HCC的新见解存在迫切的未满足的需求，这将导致新的疗法。日益增长的 另一方面，对HCC分子发病机制的了解确实为新的治疗策略打开了大门。 靶向治疗流体动力转染结合流体动力注射与睡美人 介导的体细胞整合用于长期基因表达。由于其灵活性和高效率， 现在越来越多地被用于产生研究肝癌发生的小鼠模型。 然而，到目前为止，很少有诱导系统已经建立了这项技术。扩增和 c-Myc癌基因的过度表达是HCC中最常见的遗传事件之一 c-Myc被认为是HCC的重要驱动癌基因。事实上， 小鼠肝脏中的c-Myc促进低分化HCC的形成。最近，我们发现， 消融mTORC 1的独特组分Raptor，可显著抑制c-Myc驱动的HCC 体内发育然而，目前尚不清楚mTORC 1是否是维持c-Myc HCC所必需的， mTORC 1抑制是否导致HCC消退。在本申请中，我们假设mTORC 1是 c-Myc维持所必需的;并且在肿瘤形成后删除Raptor将导致肿瘤消退。在这 R 03的小应用，我们将建立一个高效的诱导型Cre系统用于流体动力学转染（目的1）。 然后，我们将应用该技术在体内c-Myc诱导的HCC肿瘤中删除Raptor，目的是研究 mTORC 1复合物是否是维持c-Myc HCC所必需的（目的2）。总之，这是一个 自包含 符合R 03小型研究项目的描述和范围的研究项目。它除了可以 开发一种强大的研究技术，可用于表征基因的需求，或 维持HCC的途径。这些研究的结果对于建立基因或 治疗HCC的方法。