小柯机器人

法国里昂大学Patrick Mehlen等研究人员合作发现，阻断netrin-1可抑制子宫内膜癌的肿瘤生长和EMT特征。该研究于2023年8月2日在线发表于国际一流学术期刊《自然》。

研究人员描述了大多数人类子宫内膜癌（EC）中netrin-1的上调情况，并证明在EC小鼠模型中使用抗netrin-1抗体（NP137）阻断netrin-1能有效降低肿瘤的进展。接下来，研究人员在由14名晚期EC患者组成的I期试验中考察了NP137作为第一类单药的疗效。研究人员观察到8例病情稳定（14例中有8例，占57.1%）和1例符合RECIST v.1.1标准的客观反应（部分反应，14例中有1例（占7.1%），6周时靶病灶减少51.16%，随后6个月内减少达54.65%）。

为了评估NP137的作用机制，研究人员对小鼠肿瘤基因进行了分析，发现除了诱导细胞死亡外，NP137还能抑制上皮细胞向间质转化（EMT）。通过对NP137试验中的EC患者治疗前和治疗中的配对活检组织进行大量RNA测序（RNA-seq）、空间转录组学和单细胞RNA-seq分析，研究人员注意到肿瘤EMT出现了净减少。这与免疫浸润的变化以及癌细胞与肿瘤微环境之间相互作用的增加有关。

鉴于EMT对当前治疗标准的耐药性的重要性，研究人员在EC小鼠模型中显示，NP137与卡铂-紫杉醇的联合治疗效果优于卡铂-紫杉醇单药治疗。这些研究结果表明，netrin-1阻断疗法是一种临床策略，可同时触发肿瘤消蚀和EMT抑制，从而有可能减轻标准疗法的抗药性。

据介绍，作为一种原发肿瘤机制，netrin-1在癌症中上调。

附：英文原文

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

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

Issue&Volume: 2023-08-02

Abstract: 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 PhaseI trial comprising 14patients 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 6weeks and up to 54.65% reduction during the following 6months). 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 strategy triggering both tumour debulking and EMT inhibition, thus potentially alleviating resistance to standard treatments.

DOI: 10.1038/s41586-023-06367-z

Source: https://www.nature.com/articles/s41586-023-06367-z

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