Exploring the therapeutic potential of targeting mitotic exit in combination with standard of care agents in high grade B cell malignancies.

Diffuse large B cell lymphoma (DLBCL), multiple myeloma (MM) and mantle cell lymphoma (MCL) are among the most common B cell malignancies. Despite recent advances in disease management, virtually all MCL and MM patients and ±30-40% of the DLBCL patients still relapse. These 3 malignancies are all characterized by a high proliferation index, especially in the high risk/relapse setting. Blocking this uncontrolled proliferation might therefore be an interesting approach in the treatment of these diseases. In this thesis, we aim to explore the therapeutic potential of targeting proteins involved in mitotic exit in MM, DLBCL and MCL. First, the therapeutic potential of blocking the anaphase promoting complex/cyclosome (APC/C) and its co-activator Cdc20 was explored in MM, DLBCL and MCL, using the small molecule inhibitor proTAME. This inhibition resulted in a metaphase arrest, subsequently leading to (caspase-3 dependent) cell death. Secondly, the biological role of maternal embryonic leucine zipper kinase (MELK) and the therapeutic potential of MELK inhibition was examined in DLBCL and MCL. Blocking MELK, using the small molecule OTSSP167, impaired cell growth, induced caspase-mediated apoptosis and sensitized the cells to venetoclax. Moreover, OTSSP167 treatment of A20-inoculated mice resulted in a significant prolonged survival. Taken together, this study indicates that both APC/C ad MELK could be potential new targets in the treatment of these high grade B cell malignancies.