Understanding the Proteasome: From Protein Degradation to Disease Therapy
The Ernest Beutler Lecture and Prize, named for the late Ernest Beutler, MD, past president of ASH and physician-scientist for more than 50 years, is a two-part lectureship that recognizes major advances related to a single topic. This award honors two individuals, one who has enabled advances in basic science and another for achievements in clinical science or translational science.
During the last decade, proteasome inhibitors have emerged as valuable tools in the treatment of multiple myeloma and have dramatically improved the overall survival of patients as part of a wave of novel therapies for this disease. The 26S proteasome is the primary site for protein degradation in cells. It is a 60-subunit molecular machine that selectively destroys misfolded, potentially toxic proteins (e.g., abnormal immunoglobins) and most regulatory proteins by attaching them to a chain of ubiquitin molecules to target them for proteasomal destruction.
Dr. Alfred Goldberg will discuss the proteasome’s unusual mechanisms, critical functions, and the preclinical development of the proteasome inhibitors, which are now widely used in the clinic and as research tools in cell biology and immunology. He will also discuss how cells respond to reduced proteasome function and the adaptive mechanisms that can contribute to drug resistance, as well as exciting recent advances in this area that may contribute to new treatment approaches for other diseases.
Dr. Paul Richardson will focus on the preclinical and clinical development of proteasome inhibition for the therapy of relapsed or refractory multiple myeloma and its rapid integration into initial treatment as well as maintenance therapy and consolidation. He will further outline the importance and clinical benefit of combination approaches with other novel therapies, including the first-in-class boronate peptide bortezomib and second-generation agents including carfilzomib, the oral proteasome inhibitor ixazomib, and marizomib and oprozomib. Dr. Richardson will also discuss proteasome inhibition as an integral part of other future rational multiple myeloma treatments to further improve patient outcomes. This session will highlight bench-to-bedside research that has had a profound impact on the treatment of patients with hematologic diseases.