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-细胞周期蛋白（Cyclin E1、E2）调节细胞周期蛋白依赖性激酶 Cdk2 的活性，从而控制静止细胞向细胞周期 S 期的转变。因此，Cyclin E/Cdk2 复合物参与器官发育和再生的控制，但也可能在癌发生过程中发挥关键作用。大多数肝细胞癌 (HCC) 患者表现出 Cyclin E1 的过度表达。在我们自己的前期工作中，我们提供了强有力的证据，证明 Cyclin 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脏稳态来说却是可有可无的。此外，至少Cyclin E1对于恶性转化肝细胞的存活和增殖也是必需的。对于目前提出的项目，我们假设 Cyclin E1 和 Cdk2 是治疗肝脏肿瘤的新颖且有希望的靶标。该项目的总体目标是在小鼠模型中开发介入方法，通过分别急性消融 Cyclin E1 或 Cdk2 来抑制或逆转 HCC 进展。为此，我们将利用遗传（cre/loxP 介导的基因删除）、药理学（Cdk 抑制剂）和 siRNA 介导的策略。在前期工作中，我们已经建立了通过 siRNA 在小鼠体内稳定失活 Cyclin E1 的新方法。我们将比较 Cyclin E1 与 Cdk2 抑制在肿瘤消退方面的优缺点，以确定这两个靶点中哪一个最适合 HCC 的潜在治疗。此外，我们将检验我们的假设，即肝肿瘤环境的非实质细胞中的细胞周期调节和 Cyclin E1 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 Cyclin E1/Cdk2 复合物来开发治疗 HCC 的新策略。