Murine Models on SALL4 in Hepatocellular Carcinoma

SALL4 在肝细胞癌中的小鼠模型

• 批准号: 9105720
• 负责人: Li Chai
• 金额: $ 8.18万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-06 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9105720
• 关键词: Acute Myelocytic Leukemia; Albumins; Apoptosis; BAY 54-9085; Cancer Etiology; Cell Death; Cell Line; Cells; Cessation of life; Chemoembolization; Clinical; Complex; Development; Diagnosis; Disease; Down-Regulation; Drug resistance; Effectiveness; Experimental Models; Foundations; Future; Germ cell tumor; Health; Hepatocarcinogenesis; Hepatocyte; Human; In Vitro; Inner Cell Mass; Intervention; Knock-out; Knowledge; Liver; Malignant Neoplasms; Modeling; Mus; Oncogenes; Oncogenic; Operative Surgical Procedures; Oral; Pathogenesis; Pathway interactions; Patient Agents; Patients; Peptides; Pharmaceutical Preparations; Play; Population; Primary carcinoma of the liver cells; Process; Prognostic Factor; Regulation; Reporting; Role; Side; Solid Neoplasm; Somatic Cell; Staging; Stem Cell Factor; Testing; Therapeutic; Therapeutic Effect; Tissues; Transgenic Organisms; Translating; base; cancer initiation; cell growth; curative treatments; design; diagnostic biomarker; effective therapy; embryonic stem cell; gain of function; hepatocellular carcinoma cell line; improved outcome; in vivo; inhibitor/antagonist; innovation; insight; knock-down; liver transplantation; loss of function; mouse model; neoplastic cell; novel; outcome forecast; overexpression; peptide drug; pluripotency; research study; self-renewal; stem cell biology; targeted treatment; therapeutic target; therapy development; tumor growth

 DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the major malignancy of the liver; it is the third leading cause of cancer-related deaths globally. Despite advances in treatments for HCC, prognosis remains bleak, with most patients eventually dying within 2 years after diagnosis. More effective therapy for HCC is needed. The lack of effective treatment options for HCC is at least in part due to our lack of understanding the pathogenesis of this disease. Identifying novel pathway(s) that are responsible for HCC could be translated into targeted therapy and improve the outcomes of these patients. SALL4 is a stem cell factor that plays an important role during early development and is part of the key embryonic stem cell transcriptional regulatory network. SALL4 is also recognized as an oncogene and has been used as a specific diagnostic marker for various solid tumors, such as germ cell tumor and acute myeloid leukemia. Based on vigorous statistical analyses and experimental models, we have recently reported that SALL4 is an independent prognostic factor and potential therapeutic target for HCC. Importantly, we have also identified a therapeutic peptide that can effectively target the oncogenic functions of SALL4. In this RO3 application, we plan to evaluate the role of Sall4 in HCC development using both loss and gain-of function murine models. While the gain-of-function murine model will be useful to test future SALL4 inhibitors as a new class of HCC drugs, the loss-of- function murine model will help us understand whether Sall4 plays an essential role in the initiation and/or progression of HCC. The knowledge gained will help us to better understand the mechanism(s) for hepatocarcinogenesis and lay the foundation for future more efficient targeted therapy development.

 描述（由申请人提供）：肝细胞癌（HCC）是肝脏的主要恶性肿瘤;它是全球癌症相关死亡的第三大原因。尽管HCC的治疗取得了进展，但预后仍然很差，大多数患者最终在诊断后2年内死亡。需要更有效的治疗HCC。肝细胞癌缺乏有效的治疗选择至少部分是由于我们缺乏对这种疾病的发病机制的了解。识别负责HCC的新途径可以转化为靶向治疗并改善这些患者的结局。SALL 4是一种干细胞因子，在早期发育过程中发挥重要作用，是关键胚胎干细胞转录调控网络的一部分。SALL 4也被认为是一种癌基因，并已被用作各种实体瘤，如生殖细胞肿瘤和急性髓性白血病的特异性诊断标志物。基于强有力的统计分析和实验模型，我们最近报道了SALL 4是HCC的独立预后因子和潜在的治疗靶点。重要的是，我们还确定了一种治疗肽，可以有效地靶向SALL 4的致癌功能。在该RO 3应用中，我们计划使用功能丧失和获得的小鼠模型来评估Sall 4在HCC发展中的作用。虽然功能获得的小鼠模型将用于测试未来的SALL 4抑制剂作为一类新的HCC药物，但功能丧失的小鼠模型将帮助我们了解Sall 4是否在HCC的起始和/或进展中起重要作用。所获得的知识将有助于我们更好地理解肝癌发生的机制，并为未来更有效的靶向治疗开发奠定基础。