Clinical Instructor
Department of Medicine

Project Title:  Outcomes and Mechanisms of Bidirectional EphB/ephrinB2 Decoupling in Multiple Myeloma

John Chute, MD - UCLA
Ken Dorshkind, PhD - UCLA

Multidisciplinary Expertise:
Cancer biology, malignant microenvironment, stem cell regulation, hematopoietic cell transplant, chimeric antigen receptor (CAR) T-cells, clinical hematology-oncology

Project Description:
Multiple myeloma (MM) is the most common primary bone marrow malignancy and, despite advances in treatment, remains incurable. It resides almost exclusively in the bone marrow. Interactions between MM and the bone marrow microenvironment are essential for disease progression but the details of those interactions are not well understood. Bone marrow vascular endothelial cells (BMECs) strongly support myeloma and we hypothesized that this was due to a paracrine effect. Using tissue-specific endothelial cell screens and siRNA screens, we saw that the EphB/ephrinB signaling promoted MM through BMECs. EphB and ephrinB are cell surface tyrosine kinase receptors which initiate bidirectional signaling events in cells upon engagement. Loss of ephrinB2 in MM severely impaired MM growth in vivo. We will further examine the consequences of decoupling EphB/ephrinB2, evaluate the downstream molecular pathways responsible for this effect, and determine if this is a path to a pharmacologically tractable intervention.