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

• Applicant: Professor Dr. Christian Liedtke
• Subject Area: Gastroenterology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 271777553

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.

• DFG Programme: Research Grants