Sci Transl Med:这款药物或能提高胰腺癌治疗效果

2017-04-11 李华芸 学术经纬

在最近一期的《科学》子刊《Science Translational Medicine》中,一项关于胰腺癌的研究登上了封面。这项重磅研究表明,一种药物能够干扰肿瘤细胞外基质的结构,从而提高化疗等标准疗法的效果。谈到胰腺癌,许多人都不会陌生。被称为“癌症之王”的它以难治而闻名,据美国癌症学会的统计,它在术后的5年生存率只有16%。多年的研究发现,胰腺癌难治的一大原因在于它表面的致密基质。它就像是一层

在最近一期的《科学》子刊《Science Translational Medicine》中,一项关于胰腺癌的研究登上了封面。这项重磅研究表明,一种药物能够干扰肿瘤细胞外基质的结构,从而提高化疗等标准疗法的效果。

谈到胰腺癌,许多人都不会陌生。被称为“癌症之王”的它以难治而闻名,据美国癌症学会的统计,它在术后的5年生存率只有16%。多年的研究发现,胰腺癌难治的一大原因在于它表面的致密基质。它就像是一层岩石组成的外壳,阻碍了药物的渗透,也阻碍了免疫反应。因此,倘若能在肿瘤表面的基质上做些文章,也许就能提高胰腺癌的治疗效果。

来自澳大利亚Garvan医学研究中心(Garvan Institute of MedicalResearch)的一支研究团队在这一方面带来了突破。他们发现,许多肿瘤会劫持Rho GTP酶的通路,以改造细胞骨架的方式,让肿瘤变得硬化,并提高它们的生存率。因此,如果能对这条通路进行抑制,也许就会影响肿瘤组织的硬度、细胞流变学和血管舒张度,带来潜在的治疗方案。

在诸多潜在的靶点中,研究人员选择了ROCK(Rho-associated protein kinase)蛋白。这是一种与Rho GTP酶相关的蛋白激酶,有望能抑制RhoGTP酶下游的通路。此外,目前已经有了一种叫做Fasudil的ROCK抑制剂得到了美国FDA的获批上市。因此,一旦研究取得成功,研究人员就能更快将这款药物推进到临床试验阶段。

▲Fasudil结构式(图片来源:维基百科)

首先,研究人员确认,Fasudil的确对细胞外的基质有着抑制作用。一项研究表明,由于基质的完整性得到了破坏,Fasudil处理下的成纤维细胞收缩能力出现了下降。此外,免疫组化的实验结果也证实了这一点。

▲Fasudil破坏了基质完整性后,成纤维蛋白的收缩能力出现了下降(图片来源:《Science Translational Medicine》)

那么,基质完整性的丧失,是否会提高化疗药物对胰腺癌的渗透性呢?研究人员先是获取了胰腺癌的细胞株,再用Fasudil进行处理。随后,他们加上了吉西他滨和紫杉醇两种化疗药物。实验表明,在对照组中,两种化疗药物单独使用可以对胰腺癌细胞进行杀伤。而在加上了Fasudil后,这种杀伤效果得到了进一步的提升。换句话说,通过破坏基质的方法,Fasudil的确提高了化疗的效果。

▲在细胞增殖(上)和细胞凋亡(方面),Fasudil都显示出增强化疗效果的作用(图片来源:《Science Translational Medicine》)

在体外实验取得出色的成绩后,研究人员又开展了小鼠体内实验。利用CDK1作为化疗起效的标志,研究人员发现,即便是在小鼠体内,Fasudil的处理也能提高吉西他滨和紫杉醇化疗的效果。更有意思的是,无论是对原发肿瘤,还是对转移的肿瘤,它都有很好的效果。

最后,研究人员用小鼠模型,检验了Fasudil对人体肿瘤的影响。他们从患者体内分离出肿瘤细胞,并重新注入到小鼠体内,让这些肿瘤生长。研究人员发现,由于患者个体差异,不同患者体内的肿瘤细胞,基质的完整性也有着区别。一些患者的基质更完整,而另一些患者的基质则天生松松垮垮。研究表明,对那些基质天生松松垮垮的患者来说,Fasudil的提升效果并不明显。这或许是因为它们的基质无需Fasudil处理,就已经能被化疗药物渗透的关系。而对于那些基质完整的患者来说,Fasudil的处理极大地提高了化疗的作用。

▲患者本身肿瘤基质较完整的,Fasudil的增强化疗效果也越好(图片来源:《Science Translational Medicine》)

在文章最后,研究人员认为,尽管Fasudil的安全性曾在大型试验中得到了验证,它与化疗的联合治疗依旧需要通过1期临床的检验。一旦安全性得到确认,诸多胰腺癌患者就有望迎来一种提高化疗效果的新方法。

原始出处:

Claire Vennin1, Venessa T. Chin1, Sean C. Warren1,et al. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. science translational medcine. 2017 Apr.

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    2017-12-25 柳叶一刀
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    2017-04-11 doctorJiangchao

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