Epithelial–mesenchymal transition (EMT), a process by which cancer cells detach from their neighbouring cells and acquire invasive properties, plays a key role in the formation of metastases and the development of resistance to anticancer treatments. Researchers from the Université libre de Bruxelles (ULB) have now showed that Netrin-1, a molecule expressed by tumour cells in different types of cancers, stimulates EMT in tumour cells — and that a drug targeting Netrin-1 blocks EMT in cancer.
The researchers collaborated with NETRIS Pharma, which has developed a therapeutic antibody to block the interaction between Netrin-1 and its receptor, UNC5B. They showed that the administration of this therapeutic antibody — called NP137 — leads to a reduction in tumour formation and also blocks EMT in these tumours, which reduces their ability to give rise to metastases and sensitises the tumour cells to chemotherapy. Their results were published in the journal Nature.
“We are extremely happy and excited to have identified the first drug that can target EMT in vivo and therefore reduce the formation of metastases and resistance to chemotherapy,” said first author Justine Lengrand, from ULB and NETRIS Pharma.
Having demonstrated the effectiveness of the anti-Netrin 1 antibody in preventing EMT in animal models, the ULB researchers then collaborated with the Université de Lyon and NETRIS Pharma to study the effect of this drug on EMT in patients with endometrial cancers. They administered the antibody to patients in clinical trials in France, finding it was well tolerated and showed no toxicity. More importantly, they showed on biopsies from the tumours taken before and after administration of the drug that this therapy decreased EMT in patients with endometrial cancers.
“This is a major world first — we have discovered a new drug that can reduce EMT, decrease metastasis and stimulate the response to chemotherapy in preclinical models,” said ULB’s Professor Cédric Blanpain, the leader of the project. “In a second study, the researchers and clinicians provided the proof of principle for the medical application of our fundamental discovery and showed that the administration of the anti-Netrin-1 antibody inhibits EMT in cancer patients. We have now to assess whether the administration of the anti-Netrin-1 antibody and the reduction of the EMT will provide to the cancer patients a better clinical response to chemotherapy and immunotherapy.”
The collaboration has thus identified novel innovative therapeutic combinations to sensitise tumours to chemotherapy and prevent tumour progression, the development of metastases and resistance to anticancer therapy. “In the long term,” Blanpain said, “it will be necessary to determine the effectiveness of this new therapy on the survival of patients with endometrial cancers and assess this efficacy of this new drug combination for the treatment of other types of cancers presenting EMT, such as lung or breast cancers.”