Novel Treatments for Multiple Myeloma May Emerge From Ephrin B2 Research

By: Celeste L. Dixon
Posted: Tuesday, April 2, 2024

Reverse signaling of the protein ephrin B2 has been shown to be intrinsically involved in controlling the pathogenesis of multiple myeloma, according to the results of a study by Joshua P. Sasine, MD, PhD, of Cedars-Sinai Medical Center, Los Angeles, and colleagues. Disease treatment strategies—and outcomes—may be significantly improved if the mechanisms underlying this signaling pathway are identified and therapeutically targeted, which is their ultimate goal, the authors wrote in Cancer Research.

“This is the first study to identify this pathway in multiple myeloma, and the effect of inhibiting ephrin B2 on inhibiting myeloma cancer growth, suggesting a great therapeutic target for treating patients,” commented Dr. Sasine in a Cedars-Sinai press release.

The team’s work centered on a transcriptomic analysis of human bone marrow endothelial cells, which the authors stated regulate multiple myeloma’s pathogenesis and have a high capacity to promote disease growth. A complementary analysis of data on patients with multiple myeloma showed that increased expression of ephrin B2 seemed to be associated with adverse-risk disease and poorer survival.

The investigators found that multiple myeloma–supportive endothelial cells overexpressed two receptor tyrosine kinases: EPHB1 and EPHB4. What’s more, there was significantly increased expression of ephrin B2, the binding partner for EPHB1 and EPHB4, in multiple myeloma cells.

Dr. Sasine and co-researchers found that silencing EPHB1 or EPHB4 in endothelial cells suppressed multiple myeloma growth in co-culture, they explained. Furthermore, they reported the following findings:

The loss of ephrin B2 in multiple myeloma cells blocked the disease’s proliferation and survival in vitro. Administering an ephrin B2–targeted, single-chain variable fragment also suppressed multiple myeloma growth in vivo.
In multiple myeloma cells with mutant ephrin B2 that lacked reverse signaling capacity, both cell death and sensitivity to chemotherapy were increased. The mutant ephrin B2 also halted disease growth in vivo.
In contrast, overexpression of ephrin B2 in multiple myeloma cells increased STAT5 activation, increased cell survival and proliferation, and decreased sensitivity to chemotherapy.

Disclosure: For full disclosures of the study authors, visit aacrjournals.org.

Cancer Research