Multiple myeloma (MM) is dependent upon key lineage transcription factors that drive proliferation, disease progression, and drug resistance. These essential lineage factors in MM are not druggable and driven by diverse mechanisms that are not easily therapeutically targeted. A more generalizable approach is to inhibit the common chromatin remodeling complexes required for MM lineage factors. This project will target the SWI/SNF chromatin remodeling complex to determine if this is a feasible therapeutic strategy in MM and specifically in MM with t(4;14) translocations. The overall goal of this project is to generate preclinical and mechanistic data to help determine if SWI/SNF targeting agents should be tested in MM patients.
Arul Chinnaiyan, MD, PhD
Director, Michigan Center for Translational Pathology
S.P. Hicks Endowed Professor of Pathology and Urology
Howard Hughes Medical Institute Investigator
University of Michigan
Lanbo Xiao, PhD
Assistant Professor
University of Michigan
Drs. Chinnaiyan and Xiao are leading the investigation of therapeutic modalities targeting the SWI/SNF ATPase subunits SMARCA2 and SMARCA4. These studies are focused on characterizing MM cell line responses to SWI/SNF targeting agents alone and in combination with agents that target t(4;14) biology. The mechanism of action for SWI/SNF targeting agents will be investigated with an emphasis on understanding how these molecules impact essential MM lineage factors as well as the histone methyltransferase NSD2 altered in t(4;14) MM. Pre-clinical studies will be conducted using in vivo models to assess the efficacy of SWI/SNF targeting agents alone and in combination with common and experimental MM therapies to better understand how this strategy can be used to target aggressive disease including t(4;14) MM.
Leif Bergsagel, MD
Consultant, Mayo Clinic Arizona
David F. & Margaret T. Grohne Professor of Novel Therapeutics for Cancer Research
Mayo Clinic College of Medicine
Marta Chesi, PhD
Associate Consultant II
Associate Professor of Medicine
Research, Mayo Clinic College of Medicine
Drs. Bergsagel and Chesi will work with the Chinnaiyan and Xiao laboratories to leverage over 60 MM cell lines to characterize in vitro responses to SWI/SNF targeting agents alone and in combination with standard of care agents. Drs. Bergsagel and Chesi will use their Vk*MYC mouse model to assess the myeloma inhibitory effects of SMARCA2/SMARCA4 inhibition in vivo. SMARCA2/SMARCA4 inhibition will also be tested on a t(4;14) mouse model currently being developed.
Benjaman Barwick, PhD
Assistant Professor
Department of Hematology and Medical Oncology
Emory University School of Medicine
Winship Cancer Institute of Emory University
Dr. Barwick will conduct in vitro and mechanistic studies investigating SWI/SNF inhibition in combination with Immunomodulatory imide Drugs (IMiDs) to help determine if these two classes of drugs should be combined and if SWI/SNF inhibition is a feasible strategy for overcoming IMiD resistance. In collaboration with the Bergsagel and Chesi laboratories, Dr. Barwick will provide molecular correlative analyses of in vivo pre-clinical MM models treated with SWI/SNF targeting agents.