The preclinical discovery and development of bortezomib for the treatment of mantle cell lymphoma.

INTRODUCTION: Mantle cell lymphoma (MCL) is an incurable, often aggressive B-cell malignancy. Bortezomib (BTZ), the 20S proteasome inhibitor was originally developed and approved for treatment of relapsed refractory multiple myeloma, and subsequently approved for treatment of MCL. BTZ's single-agent activity induces clinical responses in approximately one-third of relapsed MCL patients. BTZ-containing combination therapies have further improved the quality and duration of clinical responses compared to standard chemotherapies in previously untreated MCL patients. Areas covered: This review summarizes the discovery, mechanisms of -action and resistance, preclinical- clinical-developments, and FDA approval of BTZ for treatments of MCL. Expert opinion: Preclinical MCL models demonstrated the apoptotic effect of BTZ through multiple mechanisms, as well as synergistic anti-MCL activity between BTZ and other chemotherapeutics. Single-agent and combinational clinical trials have validated the therapeutic potential of targeting the ubiquitin proteasome system (UPS) in MCL. However, inherent and acquired drug resistance remains a significant clinical problem and multiple potential mechanisms have been identified. Next-generation proteasome inhibitors with different pharmacodynamic properties from BTZ may partially address the issue of inherent resistance, with increased response rates noted in some diseases. In addition, upstream UPS components, e.g., E3 ligases or deubiquitinating enzymes, may also be targetable in MCL.