Netrin-1 inhibition does not attenuate cancer-induced bone pain in three translational models

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.

doi:10.64898/2026.07.10.733710

bioRxiv · 10.64898/2026.07.10.733710

Netrin-1 inhibition does not attenuate cancer-induced bone pain in three translational models

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.

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Abstract

1.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 - a humanized IGg1 monoclonal antibody) 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. Our study indicates that netrin-1 may play a role in early-stage CIBP development, but inhibition of this mechanism does not produce robust anti-nociception.

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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.. 2026-07-13. Netrin-1 inhibition does not attenuate cancer-induced bone pain in three translational models. https://doi.org/10.64898/2026.07.10.733710

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