UCLA researchers in the Department of Medicine have discovered a novel mechanism involving Eph receptor/ephrin ligand interaction, that regulates human multiple myeloma growth and repopulation in vivo.
Multiple myeloma (MM) is a plasma cell malignancy often accompanied by bone osteolytic lesions. Despite standard care with high dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT), MM remains incurable.
Eph receptors belong to a subfamily of receptor tyrosine kinases activated by ephrin ligands. Eph receptors interact with ephrins at the cell surface, triggering bidirectional signaling: forward through Eph receptors and reverse through ephrins. Cell-cell interactions through ephrin ligands and Eph receptors regulate bone cells, such as osteoblasts and osteoclasts to proliferate, migrate, attach, spread and differentiate from precursor mesenchymal or hematopoietic stem cells. It is believed that signaling mediated by ephrin ligands and Eph receptors likely modulate pathological conditions such as osteoarthritis, rheumatoid arthritis, multiple myeloma and osteosarcoma as well.
Researchers at UCLA have identified a specific Eph receptor/ephrin signaling pathway that is responsible for MM growth. Genetic silencing of this specific Eph receptor substantially inhibited the growth of human MM cells (U266, NCI-H929, and CD138+) in culture, and reduced the human MM cell growth by 5-fold in immune deficient (NSG) mice transplanted with specific Eph silenced human CD138+ MM progenitor cells. These results confirm that therapeutic targeting this specific Eph receptor is a potent strategy to inhibit human MM growth and to specifically target the MM repopulating cells that drive tumor growth in vivo. The findings also provide the impetus for the development of small molecule or other approaches to inhibit the Eph or ephrin side of this signaling pathway in MM.
Treatment of multiple myeloma and potentially other pathological conditions involving ephrin and Eph receptors mediated signaling pathway
Inhibit MM growth through a novel mechanism of action
The findings haven been tested on human MM cell lines and in mouse model.