Foretinib Is Effective Therapy for Metastatic Sonic Hedgehog Medulloblastoma
Foretinib Is Effective Therapy for Metastatic Sonic Hedgehog Medulloblastoma
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DOI：
10.1158/0008-5472.can-13-3629
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发表时间：
2015-01-01
期刊：
影响因子：
11.2
通讯作者：
Rutka, James T.
中科院分区：
文献类型：
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作者：
Faria, Claudia C.;Golbourn, Brian J.;Rutka, James T.
髓母细胞瘤是儿童最常见的恶性脑肿瘤，确诊时有转移灶，预后不良。其扩散机制知之甚少，转移灶在基因上不同于匹配的原发肿瘤。针对这两个隔室的有效且毒性较低的疗法尚未确定。在这里，我们报告了对髓母细胞瘤患者的几个大的非重叠队列的分析，发现MET激酶是Sonic Hedgehog(SHH)驱动的髓母细胞瘤的标志。在一个独立的患者队列中，对磷酸化的、活性的MET激酶的免疫组织化学分析证实了它与肿瘤复发增加和低存活率的相关性，这表明SHH髓母细胞瘤患者可能受益于MET靶向治疗。为了支持这一假说，我们在体内外实验中发现，已批准的MET抑制剂福维替尼能够抑制SHH髓母细胞瘤中MET的激活，降低肿瘤细胞的增殖，并诱导其凋亡。福维替尼可穿透血脑屏障，对原发灶和转移瘤均有效。在已建立的SHH转移性髓母细胞瘤小鼠异种移植或转基因模型中，福维替尼可减少原发肿瘤的生长，降低转移率，并增加宿主存活。综上所述，我们的结果为临床评价福维替尼作为SHH驱动的髓母细胞瘤患者的有效治疗方法提供了强有力的依据。(C)2014年AACR。
Medulloblastoma is the most common malignant pediatric brain tumor, with metastases present at diagnosis conferring a poor prognosis. Mechanisms of dissemination are poorly understood and metastatic lesions are genetically divergent from the matched primary tumor. Effective and less toxic therapies that target both compartments have yet to be identified. Here, we report that the analysis of several large nonoverlapping cohorts of patients with medulloblastoma reveals MET kinase as a marker of sonic hedgehog (SHH)-driven medulloblastoma. Immunohistochemical analysis of phosphorylated, active MET kinase in an independent patient cohort confirmed its correlation with increased tumor relapse and poor survival, suggesting that patients with SHH medulloblas-toma may benefit from MET-targeted therapy. In support of this hypothesis, we found that the approved MET inhibitor foretinib could suppress MET activation, decrease tumor cell proliferation, and induce apoptosis in SHH medulloblastomas in vitro and in vivo. Foretinib penetrated the blood-brain barrier and was effective in both the primary and metastatic tumor compartments. In established mouse xenograft or transgenic models of metastatic SHH medulloblastoma, foretinib administration reduced the growth of the primary tumor, decreased the incidence of metastases, and increased host survival. Taken together, our results provide a strong rationale to clinically evaluate foretinib as an effective therapy for patients with SHHdriven medulloblastoma. (C)2014 AACR.