James L. LaBelle, MD, PhD
Assistant Professor of Pediatrics, University of Chicago
Defining the Mechanism and Therapeutic Targets of BIM BH3-Mediated Cell Death in Diffuse Large B-cell Lymphoma
New therapies are urgently needed to treat fatal b-cell lymphomas
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy, comprising over 40% of all lymphomas. Although treatment options have expanded in recent years, cases of DLBCL are resistant to current therapies in greater than 50% of patients, requiring new targeted therapies. Dr. LaBelle’s research focuses on identifying the abnormal communication networks within DLBCL that promote their growth and treatment resistance. He hopes to translate this work into the development and application of a new therapeutic strategy to correct the molecular defects that enable these lymphoma cells to achieve immortality. BCL-2 proteins are a family of survival and death agents that regulate whether a cell lives or dies in response to stress. Lymphoma cells exploit this natural life-death balance by overproducing survival proteins and eliminating the death proteins. In particular, DLBCL has mastered how to eliminate one of the most powerful death-inducing proteins called BIM. Dr. LaBelle has applied a technology termed hydrocarbon-stapling to transform a natural protein segment of the BIM protein into a molecular tool that can identify and potentially neutralize the survival advantage of DLBCL cells. The goal of his proposal is to deploy a specialized “stapled peptide” based on the BIM protein to uncover how DLBCL cells neutralize BIM and identify the exact molecular binding partners of this novel therapeutic within these cells. He aspires to add fresh insight into the biology of DLBCL and pharmacologically replace the critical BIM functionality to overcome this often-fatal disease.