Institut Curie, Orsay, France.
INSERM U1021, Centre Universitaire, Orsay, France.
EMBO Mol Med. 2019 Aug;11(8):e9830. doi: 10.15252/emmm.201809830. Epub 2019 Jul 22.
Medulloblastoma (MB) is a pediatric tumor of the cerebellum divided into four groups. Group 3 is of bad prognosis and remains poorly characterized. While the current treatment involving surgery, radiotherapy, and chemotherapy often fails, no alternative therapy is yet available. Few recurrent genomic alterations that can be therapeutically targeted have been identified. Amplifications of receptors of the TGFβ/Activin pathway occur at very low frequency in Group 3 MB. However, neither their functional relevance nor activation of the downstream signaling pathway has been studied. We showed that this pathway is activated in Group 3 MB with some samples showing a very strong activation. Beside genetic alterations, we demonstrated that an ActivinB autocrine stimulation is responsible for pathway activation in a subset of Group 3 MB characterized by high PMEPA1 levels. Importantly, Galunisertib, a kinase inhibitor of the cognate receptors currently tested in clinical trials for Glioblastoma patients, showed efficacy on orthotopically grafted MB-PDX. Our data demonstrate that the TGFβ/Activin pathway is active in a subset of Group 3 MB and can be therapeutically targeted.
髓母细胞瘤（MB）是一种小脑的儿科肿瘤，分为四组。第 3 组预后不良，特征仍不明确。虽然目前的治疗包括手术、放疗和化疗，但往往效果不佳，而且还没有替代疗法。目前仅鉴定出少数可治疗靶向的复发性基因组改变。TGFβ/激活素途径的受体在第 3 组 MB 中很少发生扩增。然而，其下游信号通路的功能相关性及其激活尚未得到研究。我们表明，该途径在第 3 组 MB 中被激活，部分样本显示出很强的激活。除了遗传改变，我们还证明了激活素 B 的自分泌刺激是一组以高水平 PMEPA1 为特征的第 3 组 MB 中途径激活的原因。重要的是，Galunisertib 是目前正在Glioblastoma 患者临床试验中测试的同源受体的激酶抑制剂，在原位移植的 MB-PDX 中显示出疗效。我们的数据表明，TGFβ/激活素途径在第 3 组 MB 的一个亚组中是活跃的，可以作为治疗靶点。
