Translation is a physiological process frequently dysregulated in cancer cells in which the synthesis of proteins is globally increased or switched towards the specific synthesis of certain oncogenic proteins. In chronic lymphocytic leukemia (CLL), translation initiation complexes are most often overactivated following BCR involvement and abnormal kinase activity (LYN, SYK and BTK), thus leading to increased translation of oncogenic proteins.
The purpose of this project is to investigate the therapeutic efficacy and mode of action of new molecules inhibiting translation machinery and prohibitins in chronic lymphocytic leukemia (CLL), both in patient cells and in a murine model. Prohibitins are chaperone proteins that can be localized at the plasma membrane, in the cytosol or in the mitochondrial membrane. These proteins orchestrate many cellular functions such as transcription, metabolism, cytoskeletal reorganization and cell survival. In cancer cells, these proteins are also involved in the regulation of many pathways regulating translation initiation.
This project also aims to decipher, by biochemical and molecular methods, the cellular signaling pathways activated by these new molecules, alone or in combination with the BTK inhibitor ibrutinib. The project will also characterize by mass cytometry the tumor microenvironment of mice treated with combination therapies.