维奈克拉在治疗血液系统恶性肿瘤中的研究进展
Research Progress of Venetoclax in the Treatment of HematologicMalignancies
DOI: 10.12677/ACM.2023.133544, PDF, HTML, XML, 下载: 283  浏览: 608 
作者: 徐 斌：济宁医学院临床医学院，山东 济宁；张晶晶, 黄 玉, 黄 倩, 王海燕, 杨春燕, 贾 路, 吕琳琳, 李 颖, 王 健, 宋东晓, 张 颢*：济宁医学院附属医院血液科，山东 济宁
关键词: BCL-2；维奈克拉；血液系统恶性肿瘤；靶向治疗；BCL-2； Venetoclax； Hematologic Malignancies； Targeted Therapy
摘要: 细胞凋亡在恶性肿瘤的发生中起中心作用，恶性肿瘤细胞对凋亡的抵抗限制了传统细胞毒性治疗的疗效。B细胞淋巴瘤因子2 (B-cell lymphoma-2, BCL-2)蛋白家族是调控细胞凋亡内源性途径的关键因子。维奈克拉(Venetoclax, ABT-199)作为第一个上市的BCL-2选择性抑制剂，主要用于治疗急性髓系白血病(Acute Myeloid Leukemia, AML)和慢性淋巴细胞白血病(Chronic Lymphocytic Leukemia, CLL)，同时正在其他血液系统恶性肿瘤中开展的临床试验也显示出其良好的抗肿瘤特性。本文主要对BCL-2选择性抑制剂的作用机制以及目前维奈克拉在血液系统恶性肿瘤中发挥靶向治疗作用的临床数据进行总结与概述，旨在为未来维奈克拉的更进一步应用提供一定的参考依据。
Abstract: Apoptosis plays a central role in the development of malignant tumors, and the resistance of ma-lignant tumor cells to apoptosis limits the efficacy of traditional cytotoxic therapy. The B-cell lym-phoma-2 (BCL-2) protein family is a new and vital member of the endogenous apoptosis pathway. Venetoclax (ABT-199), the first BCL-2 selective inhibitor to be marketed, is primarily used for the treatment of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL), while it is also being evaluated in clinical trials for the treatment of other hematologic malignancies. This article summarizes and details the mechanism of action of BCL-2 selective inhibitors as well as existing clinical data on the targeted therapeutic effects of Venetoclax in hematologic malignancies in order to serve as a reference for future Venetoclax applications.
文章引用：徐斌, 张晶晶, 黄玉, 黄倩, 王海燕, 杨春燕, 贾路, 吕琳琳, 李颖, 王健, 宋东晓, 张颢. 维奈克拉在治疗血液系统恶性肿瘤中的研究进展[J]. 临床医学进展, 2023, 13(3): 3796-3802. https://doi.org/10.12677/ACM.2023.133544

1. 简介

细胞凋亡在恶性肿瘤的发生发展中起着中心作用，凋亡抵抗是癌细胞的标志之一，限制了传统细胞毒性疗法的疗效 [1] 。细胞凋亡受BCL-2蛋白家族中促凋亡大白和抑凋亡蛋白成员调控，后者如BCL-2、BCL-XL、MCL-1在许多血液系统恶性肿瘤中的过表达直接导致了肿瘤的发生 [2] 。维奈克拉(Venetoclax, ABT-199)是第一个上市的BCL-2选择性抑制剂，且已获得美国食品药品监督管理局(FDA)批准用于治疗急性髓系白血病(Acute Myeloid Leukemia, AML)、慢性淋巴细胞白血病(Chronic Lymphocytic Leukemia, CLL)，目前临床研究已拓展至多发性骨髓瘤(Multiple Myeloma, MM)、骨髓增生异常综合征(Myelodysplastic Syndromes, MDS)等多个血液系统恶性肿瘤，并且其范围仍在继续扩大。本文主要对BCL-2选择性抑制剂的作用机制以及目前维奈克拉在血液系统恶性肿瘤中发挥靶向治疗作用的临床数据进行总结与概述，旨在为未来维奈克拉的更进一步应用提供一定的参考依据。

2. BCL-2蛋白家族及作用机制

细胞凋亡主要由外源性和内源性两种途径诱导，外源性途径主要通过死亡受体激活，内源性途径则是由细胞应激(代谢因素、致癌基因、DNA损伤等)激活 [3] 。在细胞凋亡的内源性途径中BCL-2蛋白家族发挥了重要作用，最早的成员BCL-2在携带t(14;18)染色体异位的滤泡性淋巴瘤(Follicular Lymphoma, FL)和弥漫性大B细胞淋巴瘤(Diffuse Large B-Cell Lymphoma, DLBCL)被发现 [4] [5] ，目前已有27个基于BCL-2同源性区(BH)的BCL-2家族成员被发现。BCL-2家族成员根据功能不同可分为促凋亡蛋白和抑凋亡蛋白 [6] 。抑凋亡蛋白包含BCL-2、BCL-XL、MCL-1、BCL-W、BCL-B和BFL-1共6种，促凋亡蛋白可分为两类，一类称之为效应蛋白，即细胞凋亡的执行者BAK和BAX，另一类为BH3-only蛋白，又可分为可直接与效应蛋白BAK和BAX结合启动细胞凋亡的激活子BID、BIM [7] ，以及通过置换再激活BAK和BAX的敏感子BAD，NOXA，BMF，HRK，BIK等 [8] [9] 。细胞凋亡的内源性途径被激活后BH3-only蛋白数量增多，达到一定程度后与抑凋亡蛋白BCL-2、BCL-XL、MCL-1、BCL-W、BCL-B和BFL-1紧密结合，置换出并激活效应蛋白BAX和BAK，它们通过降低线粒体跨膜电位使线粒体外膜透化(Mitochondrial Outer Membrane Permeabilization, MOMP)，进而导致细胞色素C (CytC)、第二线粒体来源的半胱氨酸天冬氨酸蛋白水解酶激活剂(Smac/Diablo)、核酸内切酶G (endonuclease G)等促凋亡蛋白的释放 [10] ，随后细胞色素C与凋亡蛋白酶激活因子-1 (Apoptosis Protease-Activating Factor 1, APAF-1)、(d) ATP结合后形成凋亡小体招募并激活Pro-Caspase 9 [11] [12] ，形成Caspase 9全酶，进而激活细胞凋亡中的关键蛋白酶Caspase 3/6/7，启动Caspase级联反应，将核纤层蛋白(Lamin)、α微管蛋白(α-tubulin)、肌动蛋白(Actin)等底物切割成为片段，最终导致细胞凋亡 [13] [14] 。同时有研究指出，效应蛋白BAX、BAK驱动的细胞凋亡在不含有任何BH3-only蛋白的情况下也可以进行 [15] 。

BCL-2蛋白家族中促凋亡蛋白和抑凋亡蛋白之间的动态平衡与相互作用在细胞凋亡的内源性途径中起到了决定性作用。细胞凋亡是否开始取决于促凋亡信号和抑凋亡信号的调控。以BCL-2为代表的抑凋亡蛋白是细胞生存的基础，不同的细胞的生存由不同抑凋亡蛋白主导，例如成熟B淋巴细胞依赖BCL-2，浆细胞依赖MCL-1以及红细胞依赖BCL-XL [16] [17] [18] 。正常情况下的细胞凋亡应该被严格调控，但几乎所有恶性肿瘤细胞都通过高度表达抑凋亡蛋白以躲避细胞凋亡 [19] ，例如在滤泡性淋巴瘤、肺癌和乳腺癌等恶性肿瘤中高度表达的BCL-2 [4] 。除此之外，在许多恶性肿瘤中也出现了促凋亡蛋白的丢失或下调 [20] ，例如在CLL中p53的缺乏(可能由于17号染色体长臂缺失或/和p53基因突变所致)导致的NOXA能力减弱使肿瘤细胞得以逃避凋亡 [21] 。最后，通过DNA甲基化和组蛋白修饰在内的各种过程来逃避凋亡的表观遗传畸变同样是肿瘤逃避凋亡以及产生耐药的原因 [22] ，例如在慢性粒细胞白血病(Chronic Myelocytic Leukemia, CML)中可以观察到通过启动子高甲基化沉默BID和BIM促使肿瘤的发生 [23] 。基于以上的原因，开发靶向BCL-2蛋白家族以治疗原发或耐药的血液系统肿瘤的药物是当下研究的热点之一。

3. 靶向BCL-2蛋白家族的抑制剂

BH3-only蛋白可以抑制BCL-2蛋白的功能，BH3-only蛋白与BAX、BAK共同竞争BCL-2上的同一蛋白结合位点。据此理论，开发BH3-only蛋白的模拟物直接与抑凋亡蛋白如BCL-2结合，减少BAX、BAK与BCL-2的结合，将是一种促进细胞的凋亡有效方法。截至目前，凭借我们对BCL-2蛋白生物学的深入理解，加上基于其特定结构的药物设计的显著进展，已经催生了许多BCL-2抑制剂问世。ABT-737是第一个BCL-2蛋白家族抑制剂，它利用BAD的BH3区的核磁共振(NMR)结构设计，以高度的亲和力靶向BCL-2、BCL-XL和BCL-W，显示了出强大的抗肿瘤能力，然而口服利用差和水溶性低的特点限制了进一步的应用 [24] 。其衍生物ABT-263 (Navitoclax)解决了上述问题，因此成为了第一个进入临床试验的bcl-2抑制剂，在复发的慢性淋巴细胞白血病(CLL)和惰性B细胞淋巴瘤患者中均有较好的单药活性 [25] [26] [27] [28] 。然而，ABT-263也并非单一靶向BCL-2，BCL-XL同样是其靶向的目标，而BCL-XL已被证明在血小板的生存中有不可或缺的作用 [29] [30] ，因此产生的严重血小板减少限制了该抑制剂的更进一步探索。由此可见，为了更好的满足临床的需求，减少如血小板减少的副作用，进一步改善患者的预后，开发高度选择性的BCL-2抑制剂已迫在眉睫。

4. 选择性靶向BCL-2的抑制剂：维奈克拉(Venetoclax)

维奈克拉的开发为bcl-2抑制剂研究带来了新的转折点，它是Bcl-2蛋白的一种有效且高度选择性的BH3模拟物，能够避免使用Navitoclax观察到的血小板减少症 [31] 。美国食品药品监督管理局(FDA)在2016年首次批准了一项维奈克拉用于治疗复发/难治性和17号染色体缺失的CLL或小淋巴细胞淋巴瘤(Small Lymphocytic Lymphoma, SLL)患者的临床试验，表现出显著的抗肿瘤活性 [32] 。在第一个出色的发现之后，维奈克拉随即在不同的恶性肿瘤中进行了测试，均取得了令人满意的结果 [33] [34] [35] [36] 。截至目前维奈克拉单药或联合应用的临床试验仍在进行中，其结果让人期待。

2018年，FDA批准了一项联合venetoclax与低剂量阿糖胞苷(LDAC)用于治疗75岁以上的新诊断的或无法使用强化化疗的AML患者的临床试验，患者的完全缓解率(CR)达到了54%，中位生存期(OS)为10.1个月，中位缓解持续时间(DOR)为8.1个月 [37] ，2021年的一项研究人群同样是新诊断或无法使用强化化疗的老年AML患者的临床试验的结果也令人惊喜，使用venetoclax联合DNA甲基转移酶抑制剂(DNMTi)阿扎胞苷或地西他滨的患者表现出更好的CR率和更长期的OS (生存时间) [38] ，这均表明venetoclax联合DNMTi或LDAC成为了一种针对不适合强化化疗的老年特别是初治AML患者的有吸引力的化疗方式。除初治AML患者外，venetoclax在复发/耐药的AML患者中也有较好的反应，在一小群使用venetoclax作为单药治疗复发/耐药的AML临床试验中，结果发现异柠檬酸脱氢酶(IDH)1/突变的受试者比携带野生型基因的患者有更好的反应，并且更为安全。而在另一项研究中venetoclax与氟达拉滨、阿糖胞苷、粒细胞集落刺激因子和伊达柔比星组合的FLAG-IDA + VEN方案表现出更高的CR率，为接下来的干细胞移植中起到了桥梁作用 [39] 。除AML外，venetoclax也在其他血液系统肿瘤中有良好的反应，2019年，一项III期试验的结果促使欧盟委员会批准了联合venetoclax + 利妥昔单抗用于前期治疗失败复发/耐药的CLL患者 [40] ，其他联合疗法如venetoclax联合CD20单抗奥妥珠单抗或联合BTK激酶抑制剂伊布替尼的临床试验也进行了评估，均表现出较好的结果 [41] [42] 。在t(11;14)染色体易位的复发/难治MM患者的临床试验中venetoclax作为单一药物或联合地塞米松也显示出活性 [43] [44] 。尽管venetoclax在治疗初治或复发/耐药的血液系统肿瘤中显现出较好的活性，但我们也在某些经过venetoclax治疗后的CLL患者bcl-2蛋白中发现了一种药物选择的的突变(G101V) [45] ，这种突变使这些CLL患者对venetoclax耐药。除此之外，目前普遍认为抑凋亡蛋白如mcl-1和bcl-xl高表达也是耐药的原因 [46] [47] ，在AML、CLL和套细胞淋巴瘤中联合靶向mcl-1或bcl-xl的药物也已经被证实是有效解除耐药的手段 [48] [49] [50] 。因此在这里我们强调坚持研究新型Bcl-2抑制剂的必要以及联合抑制mcl-1和bcl-xl在治疗方案中的必要性。

5. 小结与展望

长期以来细胞凋亡一直被认为是肿瘤对常规化疗的反应，但它在更多的创新性治疗策略的作用中也是十分明确的。BCL-2蛋白家族在细胞凋亡的调控中起着关键作用。在过去的几十年里，大量的证据表明，不同来源的癌症，特别是血液系统恶性肿瘤，严格依赖于抗凋亡成员的生存、增殖和对治疗的反应。在这种观点下，我们进行了大量的研究以确定BCL-2抑制剂可用于治疗癌症，细胞凋亡被为使用BCL-2家族抑制剂的新疗法的鉴定。从针对bcl-2的首个药物ABT-263的临床应用开始，到FDA批准的BH3模拟药物维奈克拉，都证实了BCL-2抗凋亡成员作为治疗靶点的临床相关性。现在仍有许多临床试验正在进行中，以评估维奈克拉作为单一药物或联合其他药物治疗对血液系统肿瘤的活性。

大量的临床前研究已经积累了大量支持抗凋亡蛋白在血液系统肿瘤进展中所起作用的证据。因此，将BCL-2蛋白靶向药物作为单一药物或与目前的标准疗法联合可以为治疗耐药性/复发性血液系统肿瘤和提高患者的无病生存率提供一个机会。我们相信维奈克拉作为单一和组合药物治疗化疗敏感和耐药的血液系统恶性肿瘤的临床潜力还有待进一步研究，特别是治疗的剂量与持续时间、耐药机制等问题将是重点研究的方向。同时在不久的将来维奈克拉很可能可以成功地靶向除血液系统恶性肿瘤以外的许多恶性肿瘤，以提高治疗效果和患者生存率。

参考文献

NOTES

*通讯作者。

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