Researchers have discovered that the ephrin B2 protein may drive the growth and development of multiple myeloma and uncovered that blocking part of the protein’s unique signaling pathway may inhibit progression of the disease, according to a recent study published by Sasine et al in Cancer Research. The findings may point to an effective new therapeutic target in patients with multiple myeloma.
Background
Multiple myeloma cells—which develop inside the bone marrow—cannot survive outside of the patient. The cells rely on signals from the patient’s healthy cells to grow.
Although there are numerous treatments for multiple myeloma that may be partially effective, there is currently no cure for the disease.
“Multiple myeloma is incurable, and fundamental biological insights remain lacking in this disease,” explained senior study author John Chute, MD, Director of the Division of Hematology and Cellular Therapy at Cedars-Sinai Cancer.
Ephrin B2 is a member of the ephrin family of proteins expressed on multiple myeloma cancer cells.
Study Methods and Results
In the recent study, the researchers cultured human multiple myeloma cancer cells along with different types of blood vessel cells. They then compared the genes expressed by the blood vessel cells that did and did not spur the growth of cancer. Through a process of elimination, they were able to identify that ephrin B2 may play a role in multiple myeloma pathogenesis.
The researchers found that endothelial cells expressed unique receptors called Eph receptors—which bound with ephrin proteins expressed by multiple myeloma cancer cells to trigger cancer cell growth. Notably, the “forward signal” from the multiple myeloma cells expressing ephrin to the endothelial cells expressing Eph receptors did not significantly affect cancer growth; however, the “reverse signal” from the endothelial cells to the multiple myeloma cell was found to drive cancer growth.
Conclusions
“We showed that if we block the reverse signal of ephrin B2, … the [multiple] myeloma cells could not grow in vitro or in vivo in laboratory mice, a striking effect,” highlighted lead study author Joshua Sasine, MD, PhD, Assistant Professor of Medicine and a hematologist-oncologist at Cedars-Sinai.
Conclusions
Corresponding clinical data suggested that ephrin B2 expression may correlate with poor outcomes in patients with multiple myeloma. Given the substantial progress that has been made in the development of therapeutics to target these proteins, the ephrin B2 reverse signaling pathway may represent a novel therapeutic target for this intractable malignancy.
“This is the first study to identify this pathway in multiple myeloma, and the effect of inhibiting ephrin B2 on inhibiting [multiple] myeloma cancer growth, suggesting a great therapeutic target for treating patients,” Dr. Sasine indicated.
“Our evidence suggests the importance of the reverse signaling pathway of ephrin B2 in regulating multiple myeloma development and progression, and that inhibiting this signal in a targeted way abolishes multiple myeloma growth,” Dr. Chute underscored.
Based on the recent findings, the researchers are currently developing novel therapies to target the ephrin B2 protein in patients with multiple myeloma.
Disclosure: The research in this study was supported by grants from the National Institutes of Health, a Tower Cancer Research Foundation Career Development Award, and the ASCO Young Investigator Award. For full disclosures of the study authors, visit aacrjournals.org.
