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瘤微环境是质瘤对CSF-1R抑制的基础

Daniela F Quail¹, Robert L Bowman¹, Leila Akkari²

¹Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.

Science (New York, N.Y.)

|May 21, 2016

概括

在多种质母细胞瘤 (GBM) 中,对殖民地刺激因子-1受体 (CSF-1R) 抑制剂的耐药性是由瘤微环境驱动的. 结合针对胰岛素样生长因子-1受体 (IGF-1R) 或酸氨酸 3- 激酶 (PI3K) 的疗法和CSF-1R阻塞可以克服这种抗性.

科学领域:

癌症学
免疫学
癌症生物学

背景情况:

巨细胞在多种质母细胞瘤 (GBM) 的进展中至关重要.
在临床前模型中,针对殖民地刺激因子-1受体 (CSF-1R) 显示出对GBM治疗的希望.
在GBM中对CSF-1R抑制的抗药性机制在很大程度上仍未被探索.

研究的目的:

研究GBM中对CSF-1R阻断的产生和抵抗机制.
在GBM中确定克服CSF-1R抑制剂耐药性的治疗策略.

主要方法:

使用多种质母细胞瘤 (GBM) 的动物模型.
给药的殖民地刺激因子-1受体 (CSF-1R) 抑制剂和评估瘤反应和复发.
在复发瘤中分析了分子通路,包括酸丁3-激酶 (PI3K) 和胰岛素样生长因子-1受体 (IGF-1R) 信号.
使用CSF-1R抑制剂与IGF-1R或PI3K抑制剂的经过测试的组合疗法.

主要成果:

持续的CSF-1R抑制显著延长了生存时间,但导致超过50%的小鼠瘤复发.
发现瘤耐药性是由瘤微环境驱动的,而不是瘤细胞的内在变化.
复发性GBM表现出高酸丁3-激酶 (PI3K) 途径活性,由巨细胞衍生的胰岛素类生长因子-1 (IGF-1) 和瘤细胞IGF-1受体 (IGF-1R) 推动.
在复发瘤中,IGF- 1R或PI3K与CSF- 1R抑制的联合阻断显著改善了整体存活率.

结论:

瘤微环境对CSF-1R抑制剂的耐药性是GBM的一个重大挑战.
针对IGF-1/IGF-1R和PI3K通路与CSF-1R抑制一起,为克服GBM耐药性提供了一个有希望的治疗策略.

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