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综述 | 重组人内皮抑制素作为潜在放射增敏剂在非小细胞肺癌治疗中的应用

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  • 2023-05-15
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肺癌是全球第二常见的肿瘤[1]，其中非小细胞肺癌（NSCLC）约占所有肺癌病例的85%[2]。NSCLC的标准治疗通常包括手术、化疗、放疗（RT）、靶向治疗和免疫治疗，可单独使用或联合使用[3]；NSCLC系统治疗的最新进展得益于分子靶向治疗药物、免疫检查点抑制剂和抗血管生成药物的持续创新和改进[4,5]。


肿瘤早期可以在没有血液供应的情况下存活很长时间[6]，但随着肿瘤生长，肿瘤血管成为满足其生长和代谢的关键条件[7]；同时凋亡和坏死区域不断产生并造成的缺氧状态，成为肿瘤血管化和血管生成的始动因子[8]：缺氧环境诱导刺激低氧诱导因子1α（HIF-1α）的生成，进而导致抗血管生成因子受到抑制，同时诱导促血管生成因子的产生[9]。这种细胞因子之间的不平衡状态被喻为“血管生成的开关”，可促进肿瘤血管的生长-2。对于NSCLC，除了依赖于传统血管生成机制之外-1，也表现出了独特的特征，如血管劫持（vessel co-option）[15]，仍需在机制和治疗策略方面进一步探索。


抗血管生成药物是一种富有前景的肿瘤治疗策略[16]，旨在阻断肿瘤血管生成[17]，使肿瘤细胞处于缺氧的“饥饿”状态[18,19]。虽然这种缺氧可能会降低肿瘤细胞对辐射的敏感性，但抗血管生成治疗可以通过修剪不成熟和低效的血管使肿瘤血管“正常化”[20]，将有利于靶向药物的输送以及肿瘤部位氧浓度的增加，以提高放疗的有效性。虽然抑制和控制肿瘤血管生成作为一种独立的治疗策略可能无法治愈肿瘤，但这种疗法所具有的限制肿瘤生长和扩散的能力，以及潜在增强其他直接抗肿瘤疗法（如标准化疗和放疗）疗效的能力[21]，引起了临床的广泛关注。


目前已开展了多项研究，探讨了重组人内皮抑制素（恩度®，RE）对于化疗和放疗的增敏作用-6。近日，Pharmaceuticals（IF 5.2146）发表的一篇文章回顾和总结了内皮抑制素和RE用于NSCLC治疗的现状，特别是与放疗联合应用的相关内容[29]。


重组人血管内皮抑制素及其作用机制


内皮抑制素来自于ⅩⅧ型胶原蛋白的C端片段[30]，具有抑制新生血管的能力，可以抑制一些小鼠和人类肿瘤的生长[31,32]。RE是一种广谱血管生成抑制剂，主要抑制VEGFs和FGFs的促血管生成功能。它通过与核仁素的结合，阻止内皮细胞迁移，同时通过其他途径抑制细胞增殖（图1）-3。同时，血管内皮素与其他多种受体相互作用，也会影响内皮细胞的迁移活动。此外，还有大量的研究证实了RE其他的作用机制和对血管内皮的影响[16,37-39]，更为重要的是，相比于化疗药物RE对健康组织中内皮细胞产生的毒性作用较小[40]。


图1 重组人血管内皮抑制素的作用机制以及光子放疗和质子放疗对肿瘤血管生成的影响


放疗和抗血管生成疗法的困境


抗血管生成治疗和放射治疗的相互作用存在矛盾，因为阻断血管生成可能会加剧肿瘤内缺氧程度，降低放疗的敏感性（图2）[41,42]。氧效应是放射生物学中的一个重要概念，当使用低LET辐射时，如高能X射线，氧的存在会固定DNA自由基，从而增强放疗效果[43,44]。血管正常化理论认为抗血管生成治疗可以使肿瘤血管恢复正常状态，从而改善肿瘤缺氧，提高肿瘤的辐射敏感性（图2）-2 。但过度的抗血管生成疗法会抑制血管生成导致肿瘤内过度缺氧以及其他额外影响[45]。因此，定义正常化窗口是复杂的，这个过程非常短暂，难以捕捉[20,48,49]。


图2 重组人血管内皮抑制素与放疗的矛盾组合


RE和血管正常化


RE作为抗肿瘤药物的有效性，与其恢复血管正常化和减少HIF-1α表达及其相关信号通路的能力有关[22,50,51]。已在多项临床和动物实验中观察到RE作为血管正常化药物，在患者以及各种肺癌模型中的疗效，包括缓解肿瘤内缺氧情况、降低血管通透性和微血管密度、提高RE顺铂的协同效应等等-2；这种血管正常化能力在包括结肠癌、鼻咽癌在内的其他肿瘤模型中也得到了体现[55,56]。


RE和放疗联合治疗的临床前研究结果摘要


与RE与放疗联合治疗的临床评估相比，临床前研究较少。表1和表2总结了部分研究体外（细胞）和体内（动物模型）研究不同癌种综合效应的临床前研究。RE和放疗联合治疗引起的最明显的体外效应是细胞周期的破坏[57,58]，增强了细胞的辐射敏感性，导致细胞增殖、侵袭和迁移的改变-2。


表1  RE联合放疗的体外研究总结


表2  在体内模型使用血管内皮抑制素联合放疗的研究总结


RE和放疗联合治疗NSCLC的临床试验现状


许多临床试验和荟萃分析表明，RE治疗晚期NSCLC患者可获得明显的生存获益，且安全可耐受，包括与同期化放疗（CCRT）联合使用具有协同作用，如长春瑞滨、铂类化疗、多西他赛和依托泊苷等，这些改善和获益也见于对先前化疗耐药或完全手术切除的患者。表3列举了研究RE联合化疗或放疗/CCRT的部分临床试验概况。


表3 RE联合放疗治疗NSCLC的部分临床试验


讨论


将血管生成作为肿瘤治疗策略的目标无疑是复杂的，因为病理性的血管生成会导致肿瘤微环境发生许多变化，而化疗-抗血管生成治疗联合的潜在毒性增加、血管正常化窗口期和由此产生的氧合状态对放疗的影响也是一个问题。与质子放疗相比，光子放疗已被证实会刺激血管生成（图1）。利用RE给药后5-7天的血管正常化窗口是潜在的治疗机会；但目前尚未对RE与质子放疗联合应用的效果进行评估，据推测这种组合可能会产生协同作用，从而对血管生成产生更为强大的抑制效果。


由于一些病理特征的存在，NSCLC被认为是一种抗放射肿瘤[61,62]。一些临床试验已经证明了RE可以作为某些肿瘤的放射增敏剂（表3），同时也证实了RE与CCRT联合使用时具有协同作用。将RE和质子放疗相结合治疗NSCLC有可能提高治疗效果，特别是与免疫治疗的联合治疗。但需要更好地了解质子放疗对血管生成途径的影响，以及粒子的免疫调节作用。放疗，尤其是粒子治疗，可以激起全身性的免疫反应，这为与免疫治疗相结合提供了强有力的理由[63]，抗血管生成药物，如RE，可以通过血管正常化和优化肿瘤免疫微环境来增强免疫疗法的效果。这一原理目前被认为是一种有效的治疗策略，可以增强肿瘤免疫力，而放疗的加入可以进一步扩大NSCLC的治疗范围。


仅供医疗卫生专业人士阅读

作者：HAVAS；

审校：张小玲，张莉娟，高加索，颜爱竹；

美编：王贤；

正文图片：改编自原文；

封面图片：UgoMedia；


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