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Deleted in colorectal cancer (DCC) and uncoordinated-5 (UNC5) receptors, play a key role in tumor progression of several solid tumors by inducing apoptosis when unbound to their ligand netrin-1. Netrin 1 is currently being evaluated as a therapeutic target. These receptors, known as dependence receptors, and their ligands, have not yet been extensively explored in hematological malignancies. Here, we performed a screening of various human myeloma cell lines and bone marrow samples from multiple myeloma patients for netrin-1 and its receptors to determine the expression of netrin 1 and its receptors in multiple myeloma as well as to assess the potential anti-myeloma activity of a novel anti-netrin-1 treatment (NP137). Our results showed heterogeneous expression of netrin-1 and its receptors DCC and UNC5H2(B) in six human myeloma lines. Additionally, immunohistochemistry and flow cytometry showed expression of these molecules in a majority of myeloma patient samples.  In vitro  NP137 did not induce apoptosis of myeloma cell lines yet enhanced the cytotoxicity of bortezomib and dexamethasone.  In vivo , NP137 treatment of SCID mice with established RPMI8226 myeloma tumors led to a reduction of tumor size compared to controls.  Ex vivo , NP137 lowered the plasma cells percentage in bone marrow aspirates in a fraction of the patient samples analyzed. These results suggest that netrin signaling could constitute a novel therapeutic target in multiple myeloma.

Netrin-1 expression and targeting in multiple myeloma