Murine Models on SALL4 in Hepatocellular Carcinoma

 描述(申请人提供)：肝细胞癌是肝脏的主要恶性肿瘤；它是全球与癌症相关的死亡的第三大原因。尽管肝癌的治疗取得了进展，但预后仍然黯淡，大多数患者最终在确诊后两年内死亡。需要对肝癌进行更有效的治疗。缺乏有效的肝癌治疗选择至少部分是因为我们缺乏对这种疾病的发病机制的了解。确定与肝癌有关的新途径(S)可以转化为靶向治疗，并改善这些患者的预后。SALL4是一种干细胞因子，在早期发育过程中发挥重要作用，是胚胎干细胞转录调控网络的关键组成部分。SALL4也被认为是一种癌基因，已被用作多种实体肿瘤的特异性诊断标志，如生殖细胞肿瘤和急性髓系白血病。基于强有力的统计分析和实验模型，我们最近报道SALL4是肝癌的一个独立的预后因素和潜在的治疗靶点。重要的是，我们还确定了一种能够有效靶向SALL4致癌功能的治疗性多肽。在R03的应用中，我们计划使用功能丧失和功能获得的小鼠模型来评估Sall4在肝细胞癌发生中的作用。虽然功能获得的小鼠模型将有助于测试未来的SALL4抑制剂作为一类新的肝癌药物，而功能丧失的小鼠模型将帮助我们了解Sall4是否在肝癌的发生和/或发展中发挥重要作用。所获得的知识将有助于我们更好地了解肝癌发生的机制(S)，并为未来更有效的靶向治疗开发奠定基础。

 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.