Targeting the Unfolded Protein Response Master Regulator BiP to Induce CellDeath in Multiple Myeloma

PROJECT ABSTRACT This application describes my research on a plasma cell (PC) survival pathway in Multiple Myeloma (MM) to be performed within the context of a 5-year mentored career development plan. My ultimate goal is to become an independent physician-scientist in the area of MM as a laboratory-based Hematology/Oncology academic and to develop potential therapeutics for use in trials. Under the guidance of my primary mentors, Dr. David Allman and Dr. Alfred Garfall, at the University of Pennsylvania, I have developed a structured training plan consisting of intensive laboratory research, didactics, and oversight by an experienced faculty advisory committee. The proposed research will center on mechanisms of cell survival in MM mediated by the unfolded protein response (UPR) pathway by focusing on a key negative regulator of the pathway, BiP, and its potential as a therapeutic target. MM is an incurable plasma cell cancer that despite treatments is universally fatal. One key reason for lack of durable therapies is a limited understanding of survival pathways, such as the UPR. Professional protein secreting cells such as PCs are uniquely dependent on the UPR for survival. PCs produce 2-10,000 antibodies per second, and this extreme protein load actively engages the UPR to adapt to the stresses of high output protein production. If stress is unable to be resolved, the UPR transitions from pro-survival to pro-death. It is known that this transition occurs through gene transcription programs, but the specific programs and their time courses are unclear. I require further training in bioinformatic analysis of transcriptional datasets to tease apart this transition. The activation of these gene programs by the UPR is controlled by the negative regulator BiP. Its removal leads to UPR activation, making it both a good target to study the pro-survival to pro-death transition but also as a therapeutic target to force prolonged UPR activation and death. By using a novel BiP-targeting agent and novel MM model systems, this proposal will characterize changes in gene expression during the UPR- mediated pro-survival to pro-death transition and determine what death pathways are responsible for this transition (Aim1). It will also test the efficacy of novel BiP-targeting approaches in untreated and relapsed MM in a patient derived xenograft mouse model (Aim2). These findings will provide insight into the biology of MM survival mechanisms, provide the rationale for BiP-targeting as a therapeutic approach and provide data for larger grant applications. In undertaking the proposed studies and training plan, I will develop the skills and expertise necessary to establish an independent career in translational research.