Douyère Manon, Gong Caifeng, Richard Mylène, Pellegrini-Moïse Nadia, Daouk Joël, Pierson Julien, Chastagner Pascal, Boura Cédric
Université de Lorraine, CNRS, CRAN, UMR 7039, 54000, Nancy, France.
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Can-Cer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Bei-Jing, 100021, China.
Cancer Cell Int. 2022 Dec 1;22(1):377. doi: 10.1186/s12935-022-02796-4.
Medulloblastoma (MB) is the most common pediatric malignant brain tumor. Despite current therapies, the morbidity and recurrent risk remains significant. Neuropilin-1 receptor (NRP1) has been implicated in the tumor progression of MB. Our recent study showed that NRP1 inhibition stimulated MB stem cells differentiation. Consequently, we hypothesized that targeting NRP1 in medulloblastoma could improve current treatments.
NRP1 inhibition with a novel peptidomimetic agent, MR438, was evaluated with radiotherapy (RT) in MB models (DAOY, D283-Med and D341-Med) in vitro on cancer stem-like cells as well as in vivo on heterotopic and orthotopic xenografts.
We show that NRP1 inhibition by MR438 radiosensitizes MB stem-like cells in vitro. In heterotopic DAOY models, MR438 improves RT efficacy as measured by tumor growth and mouse survival. In addition, clonogenic assays after tumor dissociation showed a significant reduction in cancer stem cells with the combination treatment. In the same way, a benefit of the combined therapy was observed in the orthotopic model only for a low cumulative irradiation dose of 10 Gy but not for 20 Gy.
Finally, our results demonstrated that targeting NRP1 with MR438 could be a potential new strategy and could limit MB progression by decreasing the stem cell number while reducing the radiation dose.
髓母细胞瘤（MB）是最常见的儿童恶性脑肿瘤。尽管有目前的治疗方法，其发病率和复发风险仍然很高。神经纤毛蛋白-1受体（NRP1）与MB的肿瘤进展有关。我们最近的研究表明，抑制NRP1可刺激MB干细胞分化。因此，我们假设在髓母细胞瘤中靶向NRP1可以改善当前的治疗方法。
在体外对癌症干细胞样细胞以及在体内对异位和原位异种移植物的MB模型（DAOY、D283-Med和D341-Med）中，用一种新型拟肽剂MR438抑制NRP1并联合放射治疗（RT）进行评估。
我们表明，MR438抑制NRP1可使体外MB干细胞样细胞对放疗敏感。在异位DAOY模型中，通过肿瘤生长和小鼠存活情况衡量，MR438提高了放疗疗效。此外，肿瘤解离后的克隆形成试验显示联合治疗后癌症干细胞显著减少。同样，在原位模型中，仅在低累积照射剂量10 Gy时观察到联合治疗有益，而在20 Gy时则没有。
最后，我们的结果表明，用MR438靶向NRP1可能是一种潜在的新策略，通过减少干细胞数量并降低辐射剂量来限制MB的进展。
