文章：

抗血管生成治疗的抵抗模式

Modes of resistance to anti-angiogenic therapy

原文发布日期：2008-08-01

DOI: 10.1038/nrc2442

类型: Review Article

开放获取: 否

要点：

1. Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF)-mediated pro-angiogenic signalling pathways are producing demonstrable clinical benefit for an increasing number of cancer types. However, in some cases (both in humans and in mouse models of cancer) anti-angiogenic therapies produce initial responses followed almost inevitably by progression, thereby affording appreciable but limited survival advantage. In other cases there is no objective benefit. Increasing evidence supports the proposition that progression and mortality following a period of benefit reflects an adaptive response by tumours, manifesting 'evasive resistance' to angiogenesis inhibitors. By contrast, patients for whom there is no tangible benefit indicate that an intrinsic resistance to angiogenesis inhibitors exists.
2. Evasive resistance to VEGF pathway inhibitors (and arguably other angiogenesis inhibitors) involves a number of distinct and interrelated mechanisms that may be variably important. The emergent mechanisms of evasive resistance include revascularization consequent to upregulation of alternative pro-angiogenic signals; protection of the tumour vasculature either by recruiting pro-angiogenic inflammatory cells or by increasing protective pericyte coverage; accentuated invasiveness of tumour cells into local tissue to co-opt normal vasculature; and increased metastatic seeding and tumour cell growth in lymph nodes and distant organs.
3. Intrinsic resistance is likely to involve similar molecular and cellular mechanisms to those that mediate evasive resistance. Whereas rapid adaptive responses (fast evasion) may underlie some cases of apparent intrinsic resistance, there is evidence to suggest that certain tumours, owing to their stage of progression, treatment history, genomic constitution and/or host genotype, may have a pre-existing tumour microenvironment that conveys such indifference.
4. If the postulate of evasive and intrinsic resistance to angiogenesis inhibitors is further validated in preclinical and clinical investigations, we foresee a future of cancer therapeutics in which combinatorial strategies involving angiogenesis inhibition are integrated with drugs targeting resistance mechanisms to afford enduring efficacy.

要点翻译：

1. 靶向血管内皮生长因子介导的促血管生成信号通路的血管生成抑制剂，正为越来越多癌症类型带来显著的临床获益。然而，在某些情况下（包括人类癌症及小鼠癌症模型），抗血管生成治疗在产生初始应答后几乎不可避免地出现疾病进展，从而仅提供有限但可观的生存优势。另一些病例则未显现客观获益。越来越多证据支持这一观点：获益期后的疾病进展和死亡率反映了肿瘤的适应性反应，表现为对血管生成抑制剂的“逃逸性耐药”。相比之下，未获得实质获益的患者则提示存在对血管生成抑制剂的内在耐药性。
2. 针对VEGF通路抑制剂（亦可论证其他血管生成抑制剂）的逃逸性耐药涉及多种相互关联的独特机制，其重要性可能各异。新发现的逃逸性耐药机制包括：因替代性促血管生成信号上调导致的血管再生；通过招募促血管生成炎症细胞或增加保护性周细胞覆盖以实现肿瘤血管系统的保护；肿瘤细胞向局部组织侵袭能力增强以征用正常脉管系统；以及淋巴结和远处器官中转移灶定植与肿瘤细胞生长的加速。
3. 内在耐药可能涉及与介导逃逸性耐药相似的分子和细胞机制。虽然快速适应性反应（快速逃逸）可能是某些表象性内在耐药案例的基础，但有证据表明，某些肿瘤因其进展阶段、治疗史、基因组构成和/或宿主基因型，可能预先存在具有此类惰性的肿瘤微环境。
4. 若关于血管生成抑制剂逃逸性与内在耐药的假设在临床前和临床研究中获得进一步验证，我们预见未来癌症治疗将把抗血管生成联合策略与靶向耐药机制的药物相结合，从而获得持久疗效。

英文摘要：

Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signalling pathways are affording demonstrable therapeutic efficacy in mouse models of cancer and in an increasing number of human cancers. However, in both preclinical and clinical settings, the benefits are at best transitory and are followed by a restoration of tumour growth and progression. Emerging data support a proposition that two modes of unconventional resistance underlie such results: evasive resistance, an adaptation to circumvent the specific angiogenic blockade; and intrinsic or pre-existing indifference. Multiple mechanisms can be invoked in different tumour contexts to manifest both evasive and intrinsic resistance, motivating assessment of their prevalence and importance and in turn the design of pharmacological strategies that confer enduring anti-angiogenic therapies.

摘要翻译： 

靶向血管内皮生长因子（VEGF）信号通路的血管生成抑制剂，在癌症小鼠模型和越来越多的人类癌症中显示出确切的治疗效果。然而，在临床前和临床环境中，其益处至多只是暂时的，随后肿瘤生长和进展会恢复。新兴数据支持这样一种观点：两种非典型耐药模式导致了上述结果：规避性耐药——一种绕过特定血管生成阻断的适应性反应；以及内在或预先存在的无反应性。在不同肿瘤背景下，可调用多种机制来表现规避性和内在性耐药，这促使人们评估其普遍性和重要性，进而设计出能够带来持久抗血管生成疗效的药理学策略。

原文链接：

Modes of resistance to anti-angiogenic therapy