Lawrence H. Boise, PhD
Professor and Vice Chair for Basic Research, Hematology & Medical Oncology
Emory University School of Medicine
Interim Leader, Cancer Genetics and Epigenetics Research Program
Winship Cancer Institute of Emory University
Office: Winship Cancer Institute of Emory University
Phone: (404) 778-4724
Fax: (404) 778-5530
Dr. Boise received his PhD in Pharmacology and Toxicology at the Medical College of Virginia and completed his postdoctoral training in the laboratory of Craig B. Thompson, MD at the Universities of Michigan and Chicago. Dr. Boise took his first faculty position at the University of Miami where he rose to the rank of Professor of Microbiology and Immunology.
Dr. Boise moved to Emory University in 2009 as a Professor and Georgia Cancer Coalition Distinguished Cancer Scholar. He serves as Interim Leader, Cancer Genetics and Epigenetics Research Program at Winship Cancer Institute. He previously served as Graduate Program Director for the Microbiology and Immunology Graduate Program and as co-Leader of the Cancer Cell Biology Program at Winship Cancer Institute.
Dr. Boise’s laboratory studies multiple myeloma, a disease of the bone marrow that results in approximately 15,000 deaths/year in the U.S. This is a malignancy of the antibody-secreting cells of the bone marrow called plasma cells. These are long-lived cells that constitutively secrete antibodies as part of the immune defense. In myeloma, the cells have also acquired the ability to proliferate, resulting in patients having an abnormally high number of cells all secreting the same antibody. The cells have effects on both the normal bone marrow as well as the bone itself and the high levels of antibody in the blood create additional problems for patients. While there has been tremendous progress in the last 10 years, including the FDA approval of 3 new drugs, the disease remains incurable and the problems remain relapse with refractory disease.
Over the last several years, genomic profiling studies have demonstrated that multiple myeloma can be divided into 7-10 different classes of disease based on gene expression. While these subclasses have different risk with respect to survival and therapeutic responses, they have not provided great insight as to how one might treat each subclass of disease. This is in part due to the lack of druggable targets that have been identified as well as disappointing results from targeting proteins that have been identified. Dr. Boise’s laboratory has taken a different approach to try to understand how myeloma cells can be targeted by focusing on aspects of myeloma cell biology that mirror the normal biology of the plasma cell. Both the normal and malignant plasma cells are long-lived, dependent on their microenvironment, and produce, assemble and secrete antibodies and/or immunoglobulin light chains. He hypothesized that these features could provide molecular explanations to therapies that have activity as well as to clues of other means to target myeloma. His group was able to demonstrate that the activity of one of the newer agents, bortezomib (Velcade), was in part related to the protein production of cells. Specifically, that inhibition of protein degradation by this proteasome inhibitor results in the activation of an unfolded protein response and endoplasmic reticulum stress-induced responses. Since protein folding is an oxidative process, Dr. Boise hypothesized that these cells may be susceptible to oxidative stress or at least to agents that can normally be inhibited by glutathione. His team demonstrated that arsenic trioxide (Trisenox) was such an agent and that this drug had activity in a clinical trial. Currently, they are studying the role of selective autophagy in myeloma as a potential target for therapeutic intervention.
Recently, Dr. Boise’s group has been targeting the long-lived nature of the cells. This is now feasible because of the development of inhibitors of Bcl-2 proteins. The group has focused on ABT-737 since it appears to have less off-target effects than the other available compounds. However, it does not inhibit Mcl-1 and this is relevant for myeloma as Mcl-1 expression is part of normal plasma cell biology and all myeloma cell lines tested to date are dependent on Mcl-1 expression for survival. However, 3 of 6 lines were very sensitive to ABT-737 suggesting codependence of the cells on Bcl-2/xL and Mcl-1. Dr. Boise’s lab found that the interactions between Bcl-2 proteins must be analyzed to determine ABT-737 sensitivity and codependence. Specifically, they found that Bim binding to Mcl-1 predicted resistance while binding to Bcl-2/xL was associated with sensitivity. Moreover, they selected resistant lines in 4 cell backgrounds and in the cells that were initially more sensitive, the Bim was now exclusively associated with Mcl-1. In the cells where Bim was already associated with Mcl-1, the lab observed a loss of Bim expression. Interestingly, while changes were observed in Bim binding, no changes in Bak binding to Bcl-xL were observed. These studies provide insight as to how an agent like ABT-737 or the related agent in clinical trials, Navitoclax (ABT-263), could be used in an Mcl-1-dependent disease like myeloma as well as shed light on the regulation of Bcl-2 proteins in cancer.
A final area of research in Dr. Boise’s laboratory is not directly related to disease however these basic studies may also have implications in cancer. The laboratory has been studying non-apoptotic roles of proteins typically thought to be exclusively involved in apoptotic cell death. This includes the effector caspases (3 and 7) as well as Bax and Bak.