SC COBRE in Oxidants, Redox Balance, and Stress Signaling
Nathan Dolloff, PhD
Nathan Dolloff, Ph.D.
Project Title: Targeting redox regulation to overcome proteasome inhibitor resistant Multiple Myeloma.
Multiple Myeloma (MM) is a plasma cell dyscrasia and the second most common hematological malignancy in the U.S. Patient survival has significantly improved due to treatment advances, such as the development of the proteasome inhibitor bortezomib (Btz). Despite the clinical success of Btz, therapeutic resistance invariably emerges, thus marking the incurable nature of the disease. New molecular targeted treatment strategies are therefore needed, particularly those that enhance the activity of existing drugs like Btz.
Redox signaling is a particularly attractive target in the treatment of MM and other plasma cell disorders for multiple reasons. Plasma cells are the effector cells of the humoral immune response and are tasked with synthesizing and secreting immunoglobulins. The process of mass-producing bulk amounts of protein generates equimolar amounts of reactive oxygen species (ROS), making these cells vulnerable to even the slightest alterations in redox homeostasis. Secondly, the most prevalent genetic abnormality in plasma cell disorders is a chromosomal translocation involving the immunoglobulin heavy chain gene (IgH) and a region of chromosome 11q13. This translocation induces the up-regulation of 11q13 genes, one of which is glutathione S-transferase pi (GSTP), an important regulator of the cellular redox state. Further evidence comes from drug screening studies that were conducted by our group to identify chemical structures that restore Btz sensitivity to resistant cells. Interestingly, the screening hits were enriched for redox-modulating compounds (4 out of 7), suggesting that disrupting redox signaling reverses proteasome inhibitor resistance. Taken together, the redox pathway is a promising target for the treatment of plasma cell malignancies, and may be an effective therapeutic approach to combating drug resistant MM.