The Expanding Role of Proteasome-Based Therapy in the Treatment of Hematologic Malignancies

The Ubiquitin (Ub)+Proteasome pathway is the major cellular pathway for the selective degradation of nuclear and cytosolic proteins. The proteasome is the catalytic core of the Ub+Proteasome pathway and has become an intriguing new target in drug development and cancer therapy for the treatment of hematologic malignancies. Successful pharmacologic inhibition of the proteasome with the boron-containing small molecule bortezomib led to US Food and Drug Administration (FDA) approval for the treatment of multiple myeloma (MM). That clinical success has propelled tremendous interest and application of proteasome inhibition to an increasing number of hematologic malignances. Inhibition of the proteasome results in the accumulation of multi-ubiquitinated proteins that are normally degraded through the tightly regulated Ub+Proteasome pathway. Such an accumulation leads to the stabilization of numerous cellular proteins that control the cell cycle, growth, proliferation and apoptosis. It is thought that the accumulation of multi-Ub~protein conjugates leads to apoptosis although there are numerous mechanisms proposed to explain how proteasome inhibition leads to cell death. However, not all patients respond to bortezomib-based therapy and moreover, those patients that do respond inevitably develop drug resistance. In addition, the mechanism of action for bortezomib remains incompletely characterized and, thus, newer proteasome inhibitors are needed and are in clinical development. The use of the proteasome inhibitor bortezomib has been expanded successfully from MM to other hematologic malignancies that include various lymphomas, Waldenstr m’s macroglobulinemia, Amyloidosis and Acute Myeloid Leukemia (AML). The proteasome is a validated therapeutic target and proteasome inhibitors modulate protein stability to effect tumor cell growth control and promote programmed cell death. Targeting the Ub+Proteasome pathway offers great promise in the treatment of hematologic and eventually solid tumor malignancies.