Inflammation-responsive mechanisms of malignant stem cell generation and eradication in multiple myeloma
Leslie Crews
PhDUniversity of California, San Diego
Project Term: July 1, 2022 - June 30, 2027
The focus of my research is to elucidate the core molecular regulators of malignant stem cell generation in multiple myeloma. My approach addresses the tumor cell-intrinsic versus niche-dependent mechanisms of myeloma regeneration by exploring transcription factor expression and stemness profiles within single cells from primary samples and patient-derived models. The central goal of my research is to uncover novel therapeutic strategies and translate these into new myeloma treatments.
My research program centers on multiple myeloma (MM) translational research, including novel therapeutic target discovery and testing experimental treatments. There are two overall problems that my research program is addressing: 1) clinical unmet needs and 2) gaps in our understanding of myeloma biology. There is a pressing need for development of new, more selective and less toxic therapies that will complement or replace current treatment regimens, particularly for high-risk patients. Second, although the existence of myeloma-initiating stem cells has been considered for many years, the most potent disease-causing cells remain poorly defined in MM due to a lack of stable protein indicators on the surface of these cells. Thus, the central goals of my research program are to identify, characterize, and therapeutically target malignant stem-like cells in MM. To enhance identification of these relatively rare cells, we are investigating a set of stem cell-associated surface proteins whose expression is driven by inflammatory molecules. To characterize and therapeutically target disease-initiating cells in MM, we are studying the role of an inflammatory gene known as IRF4, which is abundantly expressed in myeloma cells, and also drives expression of key stem cell genes. We are studying how IRF4 supports stem cell activity in MM at a single cell level in patient samples and unique disease models. Further, my lab and our collaborators were the first to selectively block IRF4 in MM cells using an RNA-targeted agent that has now advanced to clinical trials for relapsed or refractory myeloma. We are now building on our prior studies with three distinct goals: 1) to better understand the relationship between IRF4 expression and stem cell activity in myeloma, 2) to expand the potential indications for IRF4-directed therapy to other related malignancies, and 3) to explore the role of IRF4 in non-tumor cells in the bone marrow. The overall indicators of success for my research program will be the demonstration of new biomarkers of stemness in MM, along with the successful identification of optimal combination therapy strategies involving IRF4 inhibition for future clinical development. Together, my research program will benefit blood cancer patients in the near future by refining our understanding of the inflammation-associated programs driving MM cell regeneration within the tumor microenvironment.