新型MET/TIE2/VEGFR2抑制剂altiratinib在贝伐单抗耐药的胶质母细胞瘤小鼠模型中抑制肿瘤生长和侵袭性。
Novel MET/TIE2/VEGFR2 inhibitor altiratinib inhibits tumor growth and invasiveness in bevacizumab-resistant glioblastoma mouse models.
作者信息
Piao Yuji, Park Soon Young, Henry Verlene, Smith Bryan D, Tiao Ningyi, Flynn Daniel L, de Groot John F
机构信息
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (Y.P., S.Y.P., N.T., J.F.d.G.); Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (V.H.); Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts (B.D.S., D.L.F.).
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (Y.P., S.Y.P., N.T., J.F.d.G.); Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas (V.H.); Deciphera Pharmaceuticals, LLC, Waltham, Massachusetts (B.D.S., D.L.F.)
出版信息
Neuro Oncol. 2016 Sep;18(9):1230-41. doi: 10.1093/neuonc/now030. Epub 2016 Mar 9.
BACKGROUND
Glioblastoma highly expresses the proto-oncogene MET in the setting of resistance to bevacizumab. MET engagement by hepatocyte growth factor (HGF) results in receptor dimerization and autophosphorylation mediating tumor growth, invasion, and metastasis. Evasive revascularization and the recruitment of TIE2-expressing macrophages (TEMs) are also triggered by anti-VEGF therapy.
METHODS
We investigated the activity of altiratinib (a novel balanced inhibitor of MET/TIE2/VEGFR2) against human glioblastoma stem cell lines in vitro and in vivo using xenograft mouse models. The biological activity of altiratinib was assessed in vitro by testing the expression of HGF-stimulated MET phosphorylation as well as cell viability after altiratinib treatment. Tumor volume, stem cell and mesenchymal marker levels, microvessel density, and TIE2-expressing monocyte infiltration were evaluated in vivo following treatment with a control, bevacizumab alone, bevacizumab combined with altiratinib, or altiratinib alone.
RESULTS
In vitro, HGF-stimulated MET phosphorylation was completely suppressed by altiratinib in GSC17 and GSC267, and altiratinib markedly inhibited cell viability in several glioblastoma stem cell lines. More importantly, in multiple xenograft mouse models, altiratinib combined with bevacizumab dramatically reduced tumor volume, invasiveness, mesenchymal marker expression, microvessel density, and TIE2-expressing monocyte infiltration compared with bevacizumab alone. Furthermore, in the GSC17 xenograft model, altiratinib combined with bevacizumab significantly prolonged survival compared with bevacizumab alone.
CONCLUSIONS
Together, these data suggest that altiratinib may suppress tumor growth, invasiveness, angiogenesis, and myeloid cell infiltration in glioblastoma. Thus, altiratinib administered alone or in combination with bevacizumab may overcome resistance to bevacizumab and prolong survival in patients with glioblastoma.
背景
胶质母细胞瘤在对贝伐单抗耐药的情况下高表达原癌基因MET。肝细胞生长因子（HGF）与MET结合导致受体二聚化和自磷酸化，介导肿瘤生长、侵袭和转移。抗VEGF治疗还会引发逃避性血管生成和招募表达TIE2的巨噬细胞（TEM）。
方法
我们使用异种移植小鼠模型在体外和体内研究了altiratinib（一种新型的MET/TIE2/VEGFR2平衡抑制剂）对人胶质母细胞瘤干细胞系的活性。通过检测HGF刺激的MET磷酸化表达以及altiratinib治疗后的细胞活力，在体外评估altiratinib的生物学活性。在用对照、单独使用贝伐单抗、贝伐单抗联合altiratinib或单独使用altiratinib治疗后，在体内评估肿瘤体积、干细胞和间充质标志物水平、微血管密度以及表达TIE2的单核细胞浸润情况。
结果
在体外，altiratinib在GSC17和GSC267中完全抑制了HGF刺激的MET磷酸化，并且altiratinib在几种胶质母细胞瘤干细胞系中显著抑制细胞活力。更重要的是，在多个异种移植小鼠模型中，与单独使用贝伐单抗相比，altiratinib联合贝伐单抗显著降低了肿瘤体积、侵袭性、间充质标志物表达、微血管密度以及表达TIE2的单核细胞浸润。此外，在GSC17异种移植模型中，与单独使用贝伐单抗相比，altiratinib联合贝伐单抗显著延长了生存期。
结论
总之，这些数据表明altiratinib可能抑制胶质母细胞瘤的肿瘤生长、侵袭、血管生成和髓样细胞浸润。因此，单独使用或与贝伐单抗联合使用altiratinib可能克服对贝伐单抗的耐药性并延长胶质母细胞瘤患者的生存期。
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