Netrin-1 blockade, a hope in the fight against treatment resistance

Dr Patrick Mehlen, Director of the Cancer Research Center of lyon (CRCL), and his team have made major advances in the fight against treatment resistance. Their discovery, made in association with Netris Pharma, demonstrates the crucial role of the netrin-1 protein in resistance to standard treatments, and opens up promising new therapeutic perspectives.

Chemotherapy and immunotherapy are widely used treatments for cancer. However, a significant proportion of patients develop resistance to these therapies, leading to recurrence and complicating disease management. Resistance is often linked to a biological process known as epithelial-mesenchymal transition (TEM), which is associated with tumor development, progression and metastasis, as well as resistance to standard therapies. Until now, no treatment was available to specifically block TEM and resensitize tumor cells to conventional therapies. However, Dr. Patrick Mehlen’s team at CRCL, in collaboration with biotech company Netris Pharma, has discovered a promising mechanism involving the netrin-1 protein.

In two studies published in the prestigious journal Nature, Dr. Patrick Mehlen’s team at the CRCL, in association with the biotech company Netris Pharma (a spin-off of Dr. Mehlen’s team’s academic work), has shown that the netrin-1 protein, previously known primarily for its role in embryonic development, is secreted by cancer cells to promote epithelial-mesenchymal transition. Mehlen’s team has shown that the protein netrin-1, previously known mainly for its role in embryonic development, is secreted by cancer cells to promote epithelial-mesenchymal transition. Promising results have been observed in preclinical models of endometrial cancer, where blocking netrin-1 activity led to cancer cell death and inhibition of TEM.

Read the articles here and here

Based on these findings, the authors examined the potential of NP137, a netrin-1-blocking monoclonal antibody developed by Netris Pharma. In a Phase 1 human clinical trial, NP137 was evaluated in patients with advanced endometrial cancer. Results demonstrated treatment safety, as well as anti-tumor responses in some patients, with disease stabilization and, in some cases, a reduction in metastases. In addition, preclinical model trials revealed improved performance of conventional chemotherapy treatments when combined with NP137.

In a third study, carried out by a team from the Université Libre de Bruxelles and to which Dr. Mehlen’s team made a major contribution, preclinical results show that the use of NP137 is also effective in blocking netrin-1 activity and enhancing the efficacy of conventional treatments in other cancers (skin and lung cancers).

The results of these three studies suggest that inhibition of the netrin-1 protein could be a promising approach to overcoming treatment resistance. With this in mind, a Phase II clinical trial led by Netris Pharma and the Léon Bérard Cancer Center is currently underway. This trial is evaluating the combination of drug candidate NP137 with chemotherapy and/or immunotherapy in women with gynecological cancers. The results of this crucial trial are due to be announced in mid-2024.