Journal Article

Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer

Paradisi, Andrea, Dalban, Cecile, Zindy, Egor, Hernandez-Vargas, Hector, Degletagne, Cyril, Mehlen, Patrick, Ducarouge, Benjamin, Lengrand, Justine, Bellina, Melanie, Matias-Guiu, Xavier, Bernet, Agnès, Léon, Sophie, Navaridas, Raul, Delord, Jean-Pierre, Rama, Nicolas, Mery-Lamarche, Eliane, Allard, Justine, Gheit, Hanane, Neves, David, Cassier, Philippe A., Fattet, Laurent, Braissand, Nicolas, Perol, David, Pastushenko, Ievgenia, Jelin, Remy, Salmon, Isabelle, Gadot, Nicolas, Blanpain, Cédric, Ray-Coquard, Isabelle, Garin, Gwenaële, Devouassoux-Shisheboran, Mojgan, Dolcet, Xavi, Decaestecker, Christine

2023

Overview

Netrin-1 is upregulated in cancers as a protumoural mechanism 1 . Here we describe netrin-1 upregulation in a majority of human endometrial carcinomas (ECs) and demonstrate that netrin-1 blockade, using an anti-netrin-1 antibody (NP137), is effective in reduction of tumour progression in an EC mouse model. We next examined the efficacy of NP137, as a first-in-class single agent, in a Phase I trial comprising 14 patients with advanced EC. As best response we observed 8 stable disease (8 out of 14, 57.1%) and 1 objective response as RECIST v.1.1 (partial response, 1 out of 14 (7.1%), 51.16% reduction in target lesions at 6 weeks and up to 54.65% reduction during the following 6 months). To evaluate the NP137 mechanism of action, mouse tumour gene profiling was performed, and we observed, in addition to cell death induction, that NP137 inhibited epithelial-to-mesenchymal transition (EMT). By performing bulk RNA sequencing (RNA-seq), spatial transcriptomics and single-cell RNA-seq on paired pre- and on-treatment biopsies from patients with EC from the NP137 trial, we noted a net reduction in tumour EMT. This was associated with changes in immune infiltrate and increased interactions between cancer cells and the tumour microenvironment. Given the importance of EMT in resistance to current standards of care 2 , we show in the EC mouse model that a combination of NP137 with carboplatin-paclitaxel outperformed carboplatin-paclitaxel alone. Our results identify netrin-1 blockade as a clinical strategy triggering both tumour debulking and EMT inhibition, thus potentially alleviating resistance to standard treatments. We describe netrin-1 upregulation in a majority of human endometrial carcinomas and demonstrate that netrin-1 blockade, using the anti-netrin-1 antibody NP137, is effective both in a mouse model and in patients with endometrial carcinomas.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/91 / 631/67/1517/1931 / 631/67/2329 / 64/110 / 64/60 / 692/308/575 / Animals / Antibodies / Antibodies, Monoclonal, Humanized - pharmacology / Apoptosis / Biopsy / Cancer / Cancer therapies / Carboplatin / Carboplatin - administration & dosage / Carboplatin - pharmacology / Carboplatin - therapeutic use / Carcinoma / Cell death / Disease / Disease Models, Animal / Drug Resistance, Neoplasm - drug effects / Endometrial cancer / Endometrial Neoplasms - drug therapy / Endometrial Neoplasms - genetics / Endometrial Neoplasms - immunology / Endometrial Neoplasms - pathology / Endometrium / Epithelial-Mesenchymal Transition - drug effects / Female / Gene Expression Profiling / Gene sequencing / Genes / Genotype & phenotype / Gynecology and obstetrics / Human health and pathology / Humanities and Social Sciences / Humans / Life Sciences / Medical imaging / Metastasis / Mice / multidisciplinary / Netrin-1 / Netrin-1 - antagonists & inhibitors / Paclitaxel / Paclitaxel - administration & dosage / Paclitaxel - pharmacology / Paclitaxel - therapeutic use / Patients / Pharmaceutical sciences / Pharmacology / Reduction / Ribonucleic acid / RNA / RNA-Seq / Science / Science (multidisciplinary) / Single-Cell Gene Expression Analysis / Thyroid gland / Tomography / Transcriptomics / Tumor microenvironment / Tumor Microenvironment - drug effects / Tumors / Uterine cancer