Treating Hematological Malignancies Such as Multiple Myeloma Targeting Extracellular Cyclophilin A (eCyPA) and CD147

Project Overview

• Multiple Myeloma (MM) cell interaction with bone marrow endothelial cells (BMECs) within the bone marrow microenvironment is one of the most common interactions during early stages of disease.
• The signaling molecules secreted by BMECs which promote MM disease progression are important areas of research.
• A team at Dana-Farber has identified targets, Cyclophilin A (eCyPA) and CD147, critical to the interaction of malignant myeloma cells with the bone marrow microenvironment which could be important tools in the development of novel biomarkers or therapeutics to treat the disease. 
• Dana‑Farber is interested in licensing opportunities, industry collaborations for drug development and sponsored research. 

Technology

Multiple Myeloma (MM) and other hematological malignancies are often hard to treat due disease heterogeneity, evolving drug resistance, and the lack of predictive blood based disease biomarkers. Further, the underlying disease pathogenesis in MM and other similar cancers is not fully understood; how malignant cells colonize and accumulate within the bone marrow, a critical step in disease progression, remains an area of active research. Multiple Myeloma (MM) cell interaction with bone marrow endothelial cells (BMECs) within the bone marrow microenvironment is one of the most common interactions during early stages of disease.

Researchers at Dana-Farber found Cyclophilin A (eCyPA) to be a target of the βcatenin/BCL9 transcriptional complex and identified the novel functional role of the Wnt signalling pathway in BMEC trafficking, recruitment, growth, and progression of MM. Specifically, they have identified and validated that Cyclophilin A is secreted by BMECs, promoting pleiotropic signalling changes that both enhance the migration of MM cells to the bone marrow and the proliferation of malignant myeloma cells. The binding of eCyPA to CD147 on myeloma cells leads to the activation of CD147 and the subsequent release of inflammatory cytokines, which in turn, promote the proliferation of myeloma cells and prevents their apoptosis. 

This work enables methods to identify therapeutic agents to treat multiple myeloma or other hematologic malignancies that target binding of eCyPA to CD147 and describes the administration of an inhibitor targeting eCyPA or CD147 in patients with elevated eCyPA levels. Further, this work could be utilized as preclinical assay to screen for agents that are capable of blocking proteins that slow MM cell migration, and thus represent interesting molecules for further therapeutic development. These discoveries are similarly applicable to other malignancies that exhibit high levels of eCyPA.

Further details:

Zhu D, Wang, Z, Zhao, J, et al. The Cyclophilin A-CD147 complex promotes bone marrow colonization of B-cell malignancies: implications for therapy Nat Med 21, 572–580 (2015)

Team Members: Ruben Carrasco, MD, PhD, Di Zhu,PhD

Applications

• Therapeutic method of use in eCyPA high cancers, including leukemia, lymphoma, pancreatic cancer, breast cancer, colorectal cancer, and glioblastoma multiforme.  
• Diagnostics 
• Treatment selection, treatment, response to treatment 

Opportunities

Dana‑Farber is interested in licensing opportunities, industry collaborations for drug development and sponsored research. 

Team Members

Ruben Carrasco, MD, PhD

Investigator, Department of Pathology, Dana-Farber

Professor of Pathology, Harvard Medical School

Ruben's Bio

Di Zhu,PhD

Former Postdoctoral Research Fellow, Ruben Carrasco Lab, Dana-Farber

Di's Bio