SC COBRE in Oxidants, Redox Balance, and Stress Signaling
Nathan Dolloff, PhD
Nathan Dolloff, Ph.D.
2010 Postdoctoral Fellowship, University of Pennsylvania
2007 Ph.D., Drexel University College of Medicine
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 and other drugs in its class, 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 proteasome inhibitors.
My lab has designed and implemented high throughput drug screening methods for discovering small molecules that restore sensitivity to proteasome inhibitors in resistant MM cells. Our screening efforts have identified a class of molecule (known as E61) with selective MM cytotoxicity and the ability to enhance proteasome inhibitor induced MM cell death in a heterogeneously diverse panel of MM cells. E61 is well tolerated in mouse models of MM and shows strong efficacy for an early stage lead. We have leveraged institutional and COBRE programmatic strengths in mass spectrometry, redox bioanalytics, molecular imaging, and bioenergetics to identify the mechanism of action of E61. This has led us to a novel molecular target that is a key mediator of cellular protein folding, an attractive mechanism in MM given the sensitivity of this disease to proteotoxic stressors. Disruption of protein homeostasis by E61 leads to a robust ER stress and oxidative stress response, which is further compounded by the combination with proteasome inhibitors. We are currently pursuing the commercial development of proprietary E61 analogs, and in parallel, investigating the molecular target of E61 as a new and promising therapeutic target for the treatment of MM. Other myeloma drug discovery projects in the lab include the development of high throughput assays measuring anti-myeloma T cell responses. The ultimate goal of this project is to identify compounds that enhance immuno-oncology therapies including checkpoint inhibitors and adoptive T cell approaches.