Science Advances:颠覆癌症研究:抗癌药临床前效果突出,上临床就不行了,问题出在氧气浓度上?

2022-01-20 nagashi “生物世界”公众号

众所周知,癌细胞有着与正常细胞不同的代谢活动。因此,靶向癌症相关的代谢通路已成为治疗癌症的有效方法。但值得注意的是,许多靶向药物在临床前研究中表现出优异的治疗效果,却在后续的临床研究中遭遇“滑铁卢”。

众所周知,癌细胞有着与正常细胞不同的代谢活动。因此,靶向癌症相关的代谢通路已成为治疗癌症的有效方法。但值得注意的是,许多靶向药物在临床前研究中表现出优异的治疗效果,却在后续的临床研究中遭遇“滑铁卢”。

近日,美国印第安纳大学医学院的研究团队在 Science 子刊 Science Advances 上发表了题为:Tumor collection/processing under physioxia uncovers highly relevant signaling networks and drug sensitivity的研究论文。

该研究表明,在临床前研究中,培养的癌细胞大多处于比较高的空气氧浓度(21%氧气浓度),而实际上体内的肿瘤通常处于缺氧状态(1%-2%氧气浓度),这种氧浓度差异在很大程度上影响了癌细胞对靶向药物的敏感性。

原发性肿瘤的临床前研究通常是在空气氧浓度(21%)的条件下进行培养的,然而,器官中的氧气浓度通常在3-10%,大多数肿瘤更是处于缺氧或1%-2%的氧气环境中。此前,不少研究已经注意到氧气浓度对体外培养的肿瘤细胞的特性有影响,但这些研究都是在肿瘤首次被收集并在空气中处理后才进行的。

本研究的通讯作者、印第安纳大学教授 Harikrishna Nakshatri 博士表示:“我们身体各个部位的氧气水平几乎是空气氧浓度的一半以下,氧气浓度对肿瘤中不同蛋白质的功能有不同的影响。这项研究表明——我们需要改变收集肿瘤组织和测试药物敏感性的研究方式。”

氧气对细胞的生理活动有着举足轻重的影响,相同的蛋白在不同的氧浓度下可能有着不一样的生理活性——它们可能被激活、失去或降低活性、也可能没有什么变化。因此,如果能以一种更接近肿瘤在体内的状态的方式来检验肿瘤对药物的敏感性,那么相应的临床前研究将更能反映真实疗效。

本研究的实验流程图,physioxia:生理缺氧;ambient:空气氧浓度

研究团队在两种不同类型的肿瘤上测试了三种不同的药物。他们将肿瘤培养物一分为二,其中一部分在5%的氧气浓度下培养,另一部分在空气氧浓度(21%)下培养,然后测试两者对药物的敏感性。

研究人员发现,与空气氧浓度相比,在5%氧气浓度的低氧环境下收集、处理和培养的原发性肿瘤在关键信号通路网络中表现出明显的差异,包括LGR5/WNT、YAP和NRF2/KEAP1、细胞核活性氧类型、可变剪接以及对靶向治疗的敏感性。

在原发性肿瘤收集和培养过程中,不同氧气浓度对其信号网络的影响

简而言之,在不同的氧气浓度环境下,肿瘤细胞的生理状态以及对药物的敏感性水平是不同的!

对此,Harikrishna Nakshatri 教授说道:“现在,我们的研究提出了更多亟待回答的问题。为什么不同氧浓度下的肿瘤细胞对药物的反应会不同?我们之前筛选抗癌药物的方法正确吗?如果我们在生理氧水平上筛选药物,我们是否能找到更多有效的抗癌药物?”

在低氧浓度和空气氧浓度下的癌细胞显示不同水平的额外细胞表面标记物

从这一研究结果来看,这些年来,医学科学家在21%的空气氧浓度下做的临床前研究实验可能错过了一些原本对肿瘤有良好疗效的抗癌药物,当然,也筛到了很多在生理条件下对肿瘤无效的药物。

瘤细胞在低氧浓度和空气氧浓度下的生长特性不同

研究团队计划继续研究肿瘤对其他不同氧水平的不同反应。Harikrishna Nakshatri 教授表示,假设我们在空气氧浓度下确定了一种有效的抗癌药物,那么还需要在实验室中增加另一项试验——在生理低氧水平下再次验证这种药物的有效性。如果它仍然有效,就可以向前推进到临床试验,这将大大增加了药物成功的机会!

原始出处:

BRIJESH KUMAR, et al. Tumor collection/processing under physioxia uncovers highly relevant signaling networks and drug sensitivity. SCIENCE ADVANCES, 12 Jan 2022, Vol 8, Issue 2.

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    2022-01-21 sunylz
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    2022-01-21 jichang
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    2022-01-20 12116ff9m13(暂无昵称)

    特别好

    0

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