Novel Strategies in the Treatment of Multiple Myeloma: From Proteasome Inhibitors to Immunotherapy

Abstract

The proteasome serves as the catalytic core of the Ubiquitin (Ub) protein degradation pathway and has become an intriguing target in drug development and cancer therapy. Successful pharmacologic inhibition of the proteasome with the small molecule bortezomib led to US Food and Drug Administration (FDA) regulatory approval for the treatment of mantle cell lymphoma and multiple myeloma (MM) and has been extended to a steadily increasing number of clinical trials to assess effi cacy and safety in other hematologic malignances and solid tumors. Proteasome inhibition results in the accumulation of multi-ubiquitinated proteins, which are normally degraded through the tightly regulated Ub pathway. The Ub-Proteasome pathway is responsible for the selective degradation of many proteins that regulate the cell cycle and growth. Inhibition of the proteasome generates the accumulation of multi-ubiquitinated proteins that eventually leads to apoptosis although the exact mechanism of cell death is not completely understood. A specialized form of the proteasome, known to as the immunoproteasome, processes intracellular and viral proteins to generate peptides that are then presented at the cell surface bound as antigens (Ags) bound to the Major Histocompatibility Complex (MHC) class I molecule receptor. Importantly, inhibitors of the immunoproteasome decrease the processing and generation of MHC class I Ags and alter tumor cell recognition by the principal cellular effectors of the immune system. Hence, proteasome inhibitors may be employed as therapeutics to regulate the production of tumor specifi c Ags and for the selective removal of tumor cells through recognition by cytotoxic T lymphocytes (CTLs), natural killer (NK) cells and dendritic cells (DC). Proteasome inhibitors have been validated as effective cytotoxic agents and may have further potential as novel immunotherapeutic strategies.