IGF1RHC · Targeting IGF-1 receptor in liver cancer with focus on its mechanistic role in transcription and its interaction with the cell cycle machinery

The insulin-like growth factor-1 receptor (IGF-1R) is a cell surface receptor kinase being vastly expressed in malignant tissues and plays crucial roles in growth and survival of cancer cells. Targeting IGF-1R is pharmaceutically today a very attractive concept. Larsson’s group at KI has contributed extensively to the current knowledge about IGF-1R and demonstrated that the cyclolignan PPP inhibits IGF-1R signaling. An oral IGF-1R inhibitor of cyclolignan chemistry is presently studied in patients with advanced cancer. Recently, they found that IGF-1R is SUMOylated, translocated to the nucleus, where it affects transcription. This is a novel and original function for IGF-1R and one of the goals of this proposal is to further study whether it is limited to tumor cells. In such case, these findings will be a breakthrough and the foundation for further development of specific therapeutic targeting of cancer. Here we aim to study two mechanistic aspects of IGF-1R: (1) its role as a transcription factor in tumor cells, (2) its interaction with the cell cycle machinery, as ultimate regulators of cell division. Hepatocellular carcinoma (HCC) was chosen as it has a very poor prognosis and a high mortality due to absence of efficient treatments. It is one of Egypt’s national health priorities and its incidence is increasing in Europe. Three experimental models will be used : HCC cell lines in which SUMOylation, nuclear translocation of IGF-1R and, which genes it transcriptionally activates will be studied, We will induce HCC in knockout mice lacking Cdk2 and p27, generated by Aleem to study how IGF-1R interacts with loss of these cell cycle proteins, and how its inhibition by PPP affects development and progression of HCC. Mouse Embryo Fibroblasts isolated from these mice will also be used for cell cycle analysis. We anticipate that IGF-1R modulates transcription of genes relevant to tumor growth leading to development of more specific therapeutic tools against liver cancer