Hopkins, C.; Brandt Lassen, M.; Ploug Hansen, L.; Tang, Y.; Ciputra, E.; Lund Jorgensen, T.; Haaber Christensen, M.; Pedersen, C. L.; Svensson, C.; Ding, M.; Pedersen, R. S.; Willumsen, N.; Heegaard, A.-M.

Cancer-induced bone pain (CIBP) occurs in a majority of patients when primary or metastatic cancer develops within the bone. This pain has a significant impact on quality of life, yet there are limited effective treatment options available. Nerve sprouting is a complex mechanism that has been implicated in CIBP. Netrin-1 is a neuronal guidance molecule that is produced by numerous cell types, including cancer cells. In this study we aimed to determine whether netrin-1 inhibition (with NP137) could ameliorate nerve sprouting, and nociception by extension, in three models of CIBP -- osteosarcoma, metastatic breast cancer, and metastatic prostate cancer. Sustained administration of NP137 failed to produce an anti-nociceptive effect in these models, but a delayed onset was observed in the osteosarcoma model. NP137 did not produce a disease-modifying effect, as micro-computed tomography did not reveal reduced bone destruction in the NP137-treated groups. Additionally, there was no nerve fibre density reduction in any of the groups at the late-stage of the disease, suggesting that nerve sprouting occurs in early- to mid-stage CIBP development. Investigation of NP137 exposure indicated that serum levels of NP137 were comparable between the sham and cancer groups, and NP137 was detected in the bone environment of NP137-treated mice. Our study indicates that netrin-1 may play a role in early-stage CIBP development, but inhibition of this mechanism does not produce anti-nociception.