Inhibition of netrin to sensibilize cancer to chemotherapy and immunotherapies: from bench to bedside
Netrin-1, which is expressed mainly during embryonic development, is re-expressed by both cancer cells and the tumour microenvironment in a large proportion of human neoplasms. In non-clinical models, interference between netrin-1 and its receptors is sufficient to trigger cancer cell death and induce tumour growth inhibition. A netrin-1-blocking humanized monoclonal antibody (NP137) was developed by Netris Pharma and is currently in clinical trial as a monotherapy in solid tumours (ClinicalTrials.gov identifier NCT02977195).
In the Nature publication by Lengrand et al, the laboratory of Cedric Blanpain (WEL Research – ULB) studied the role of netrin during epithelial-mesenchymal transition (EMT). EMT, a process by which cancer cells detach from their neighboring cells and acquire invasive properties, plays a key role in the formation of metastases and the development of resistance to anti-cancer treatments. The researchers found that netrin-1 was upregulated in a mouse model of skin squamous cell carcinoma (SCC) exhibiting spontaneous EMT. Pharmacological inhibition of netrin-1 by administration of NP137 decreased the proportion of EMT tumour cells in mouse skin SCC, decreased the number of metastases and increased the sensitivity of tumour cells to chemotherapy.
In the back-to-back Nature publication by Cassier et al, the group of Patrick Mehlen (University of Lyon, France), in collaboration with the Blanpain laboratory, reported translational data generated in parallel with the on-going Phase 1 study including patients with endometrial carcinomas (ECs). The researchers provided a series of preclinical and biopsy data demonstrating that NP137 not only reduced tumour cell number but also triggered inhibition of EMT features, which ultimately increased tumour sensitivity to chemotherapy.
These results showed that blockade of netrin with NP137 decreased resistance to anti-cancer treatments by a mechanism that involves EMT inhibition, providing strong scientific rational to the on-going combination clinical trial with NP137 (NCT04652076).
Reference :
- Lengrand et al, Pharmacological targeting of netrin-1 inhibits EMT in cancer, Nature (2023) 620: 402-408
- Cassier et al, Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer, Nature (2023) 620: 409-416
Source : Press release ULB
