Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer.
1. Nature. 2023 Aug;620(7973):409-416. doi: 10.1038/s41586-023-06367-z. Epub 2023 Aug 2. Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer. Cassier PA(1), Navaridas R(#)(2), Bellina M(#)(3)(4), Rama N(#)(3), Ducarouge B(#)(4), Hernandez-Vargas H(#)(5), Delord JP(#)(6), Lengrand J(3)(4)(7), Paradisi A(3), Fattet L(3), Garin G(1), Gheit H(1), Dalban C(1), Pastushenko I(7), Neves D(3), Jelin R(3)(4), Gadot N(8), Braissand N(3)(4), Léon S(8), Degletagne C(8), Matias-Guiu X(2), Devouassoux-Shisheboran M(9), Mery-Lamarche E(10), Allard J(11), Zindy E(11), Decaestecker C(11)(12), Salmon I(11)(13)(14), Perol D(1), Dolcet X(2), Ray-Coquard I(1), Blanpain C(7), Bernet A(15)(16), Mehlen P(17)(18). Author information: (1)Centre Léon Bérard, Departement de Recherche Clinique, Centre de recherche en cancérologie de Lyon INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard, Lyon, France. (2)Basic Medical Sciences Department Oncological Pathology Group, Institut de Recerca Biomèdica de Lleida, Universidad de Lleida, Lleida, Spain. (3)Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Institut PLAsCAN, Centre de Recherche en Cancérologie de Lyon INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard, Lyon, France. (4)Netris Pharma, Lyon, France. (5)Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR 5286, Centre Léon Bérard, Claude Bernard Lyon 1 University, Lyon, France. (6)Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France. (7)Laboratory of Stem Cells and Cancer, WEL Research Institute, Université Libre de Bruxelles, Brussels, Belgium. (8)CRCL Core facilities, Centre de Recherche en Cancérologie de Lyon (CRCL) INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard, Lyon, France. (9)Hospices Civils de Lyon, Department of Pathology, Lyon, France. (10)Department of Pathology, IUCT-Oncopole, Toulouse, France. (11)DIAPath, Center for microscopy and molecular Imaging, Université Libre de Bruxelles, Gosselies, Belgium. (12)Laboratory of Image Synthesis and Analysis, Ecole Polytechnique-Université libre de Bruxelles, Brussels, Belgium. (13)Departement of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium. (14)Centre Universitaire Inter Régional d'Expertise en Anatomie pathologique Hospitalière (CurePath), Jumet, Belgium. (15)Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Institut PLAsCAN, Centre de Recherche en Cancérologie de Lyon INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard, Lyon, France. agnes.bernet@lyon.unicancer.fr. (16)Netris Pharma, Lyon, France. agnes.bernet@lyon.unicancer.fr. (17)Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Institut PLAsCAN, Centre de Recherche en Cancérologie de Lyon INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard, Lyon, France. patrick.mehlen@lyon.unicancer.fr. (18)Netris Pharma, Lyon, France. patrick.mehlen@lyon.unicancer.fr. (#)Contributed equally Comment in Nat Rev Drug Discov. 2023 Oct;22(10):785. doi: 10.1038/d41573-023-00137-2. J Immunother Cancer. 2024 Apr 4;12(4):e008937. doi: 10.1136/jitc-2024-008937. Netrin-1 is upregulated in cancers as a protumoural mechanism1. 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 care2, 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
