Therapy of Hepatocellular Carcinoma through targeted inhibition of the cell cycle mediators Cyclin E1 and Cdk2 in mouse models

通过靶向抑制小鼠模型中的细胞周期介质 Cyclin E1 和 Cdk2 来治疗肝细胞癌

• 批准号: 271777553
• 负责人: Professor Dr. Christian Liedtke
• 金额: --
• 依托单位: Klinik für Gastroenterologie, Stoffwechselerkrankungen und Internistische Intensivmedizin (Med. Klinik III)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/271777553?language=en
• 关键词: Therapy; Hepatocellular; Carcinoma; through; targeted

E-cyclins (Cyclin E1, E2) regulate the activity of the cyclin-dependent kinase Cdk2 and thereby control the transition of quiescent cells into the S-phase of the cell cycle. Therefore, the Cyclin E/Cdk2 complex is involved in the control of organ development and regeneration, but may also have a crucial role during carcinogenesis. The majority of patients with Hepatocellular Carcinoma (HCC) show over-expression of Cyclin E1. In own preliminary work we provided strong evidences that Cyclin E1 and Cdk2 are essential for the development of HCC in mouse models, while they are dispensable for liver regeneration and liver homeostasis. In addition, at least Cyclin E1 is also essential for survival and proliferation of malignant transformed hepatocytes. For the present proposed project we hypothesize that Cyclin E1 and Cdk2 are novel, promising targets for the therapy of liver tumors. The overall aim of this project is the development of interventional approaches in mouse models for the inhibition or reversion of HCC progression by acute ablation of Cyclin E1 or Cdk2, respectively. To this end we will take advantage of genetic (cre/loxP mediated gene deletion), pharmacological (Cdk inhibitors) and siRNA-mediated strategies. In preliminary work we already established novel methods for stable inactivation of Cyclin E1 through siRNA in mice. We will compare the advantages and disadvantages of Cyclin E1 versus Cdk2 inhibition for the tumor regression in order to define which of the two targets might be most suitable for a potential therapy of HCC. In addition we will test our hypothesis that cell cycle regulation and Cyclin E1 expression in non-parenchymal cells of the hepatic tumor environment may also affect hepatocarcinogenesis. In summary the present project aims to develop novel strategies to cure HCCs by effective inhibition of the Cyclin E1/Cdk2 complex.

E-Cyclin（Cyclin E1，E2）调节细胞周期蛋白依赖性激酶CDK2的活性，从而控制静态细胞向细胞周期的S期过渡。因此，细胞周期蛋白E/CDK2复合物参与器官发育和再生的控制，但在癌变中也可能具有至关重要的作用。大多数肝细胞癌（HCC）患者表现出细胞周期蛋白E1的过表达。在自己的初步工作中，我们提供了有力的证据，即旋风E1和CDK2对于小鼠模型中HCC的发展至关重要，而它们对于肝脏再生和肝稳态是可分配的。另外，至少Cyclin E1对于恶性转化的肝细胞的生存和增殖也至关重要。对于本提议的项目，我们假设细胞周期蛋白E1和CDK2是新颖的肝肿瘤治疗的有希望的靶标。该项目的总体目的是在小鼠模型中开发介入的方法，分别通过急性消融Cyclin E1或CDK2抑制HCC进展。为此，我们将利用遗传（CRE/LOXP介导的基因缺失），药理学（CDK抑制剂）和siRNA介导的策略。在初步工作中，我们已经建立了通过小鼠中siRNA稳定灭活细胞周期蛋白E1的新方法。我们将比较细胞周期蛋白E1的优势和缺点与肿瘤回归的CDK2抑制作用，以定义两个目标中的哪个最适合于HCC的潜在治疗。此外，我们将检验我们的假设，即肝肿瘤环境的非核素细胞中细胞周期调节和细胞周期蛋白E1的表达也可能影响肝癌的发生。总之，本项目旨在通过有效抑制细胞周期蛋白E1/CDK2复合物来制定新的策略来治疗HCC。