药物资讯  >> Vol. 9 No. 2 (March 2020)

药物治疗胶质瘤相关机制研究进展
Research Progress of Related Mechanisms about Treatment of Glioma by Medicine

DOI: 10.12677/PI.2020.92012, PDF, HTML, XML, 下载: 169  浏览: 331 

作者: 张莹莹*, 童 玥:中国药科大学生命科学与技术学院,江苏 南京

关键词: 肿瘤侵袭胶质瘤肿瘤抑制剂Tumor Invasion Glioma Tumor Suppressor

摘要: 胶质瘤恶性程度高,容易侵袭和转移,手术治疗、放射疗法和药物治疗是目前最常用的治疗方式,而由于胶质瘤易侵袭,病灶与周围正常组织边界不清晰,手术治疗很难将肿瘤病灶完全清除,放射疗法对身体伤害大,成本高,因此药物辅助治疗就显得尤为重要。目前,研究中或已上市的针对胶质瘤的化疗药物或单抗类药物繁多,作用的靶点也不甚相同,本文就药物治疗胶质瘤最新的相关机制进行了综述。
Abstract: High degree of malignancy and easy to invade and metastasize are the characteristics of glioma, and the common methods used to treat glioma are surgery, radiation therapy, and medication now. The first treatment is difficult to completely remove lesions, because the boundary between tumor and surrounding normal tissues is not clear. The second therapy is harmful and costly. So medical treatment is particularly important. At present, there are many chemotherapeutic drugs or mono-clonal antibodies with different mechanisms of action in the research or market. This article summarizes the latest relevant mechanisms of drug treatment for glioma.

文章引用: 张莹莹, 童玥. 药物治疗胶质瘤相关机制研究进展[J]. 药物资讯, 2020, 9(2): 78-84. https://doi.org/10.12677/PI.2020.92012

1. 引言

胶质瘤是恶性程度最高的中枢神经系统肿瘤 [1],位列最致命的人类恶性肿瘤之一,原发于颅内,由于其具有高侵袭力、高浸润性且易转移的特点,其患者生存率往往较低,两年生存率低于26.5% [2]。根据恶性程度,世界卫生组织将胶质瘤共分为I~IV级,恶性程度逐渐增加。原发性胶质母细胞瘤恶性程度最高,无进展生存期中位数为6.9个月,即使采用标准的手术疗法,放射疗法和替莫唑胺辅助治疗,中位总体生存期仅为14.6个月 [3]。因此寻找合适的治疗靶点或有效的信号通路就尤为重要。

2. 细胞因子

2.1. 血管内皮生长因子

血管内皮生长因子(vascular endothelial growth factor, VEGF)是高度保守的同源二聚体糖蛋白,其基因由8个外显子和7个内含子组成。胶质瘤恶性程度高,肿瘤细胞生长速度快,具有易转移和易侵袭的特点,这些都依赖于VEGF诱导的新生血管的生成。肿瘤组织活检分析发现,胶质瘤患者后期EGFRvIII发生突变,进而激活相关的信号通路,促进血管生成,增加肿瘤的恶性程度 [4]。VEGF的受体VEGFR1和VEGFR2可以通过自分泌的方式进行信号传导,从而在体外环境中调节肿瘤细胞的增殖能力,克隆形成能力和转移能力;在体内试验中抑制VEGFR1或(和) VEGFR2可以显著延长小鼠的生存期(P < 0.5) [5]。肿瘤细胞大多生长速度快,增殖能力强,采用无氧呼吸即沃伯格效应,组织缺氧使得缺氧诱导因子(HIF-1)激活,而HIF-1可以直接调控转录辅助因子Limb-Bud and Heart (LBH)的表达。研究发现,在神经胶质瘤中,LBH过表达时通过VEGFA介导细胞外调节激酶(ERK)信号的转导,促进血管生成和HIF-1表达,而HIF-1进一步调控LBH形成反馈环,并导致自我恶性循环增强。抑制VEGFA,在一定程度上可以降低细胞的增殖能力,延缓肿瘤进展 [6]。肿瘤的发生发展与其所处的微环境密切相关,有研究表明,神经胶质瘤中小胶质细胞/巨噬细胞对血管生成有促进作用,但胶质瘤中VEGF过表达明显抑制小胶质细胞/巨噬细胞的积累和聚集及免疫调节因子的表达,表明VEGF是胶质瘤中先天性免疫的调节剂,可抑制小胶质细胞/巨噬细胞对血管的促生成作用,从而抑制肿瘤生长 [7]。已上市的针对VEGF的人源化单克隆IgG抗体贝伐单抗,2009年被批准用于复发性胶质瘤 [8],临床数据表明,贝伐单抗可延长患者生存期,在临床治疗中可以改善生存趋势 [9]。因此VEGF及其受体VEGFR是胶质瘤治疗的有效靶点。

2.2. 转化生长因子-β

转化生长因子-β可以影响细胞的生长、分化、迁移等生理活动,也是参与多种病理过程的生长因子,其与上皮-间充质转化(EMT)相关 [10],并且大量证据表明TGF-β在神经胶质瘤微环境中表达丰富并且对于神经胶质瘤的侵袭至关重要 [11],被认为是治疗胶质瘤的靶标,某些情况下,TGF-β通过与长的非编码RNA (lncRNA)相互作用而进行信号传导 [12]。胶质瘤中,lncRNA LINC00115高表达,TGF-β上调 LINC00115,促进干样细胞的自我更新和肿瘤的形成 [13]。TGF-β的亚型之一TGF-β2会诱发自噬,在胶质瘤中,TGF-β2可以通过Smad通路或非Smad通路改变EMT和细胞代谢,尤其是影响线粒体运输和膜电位,进而改变细胞的侵袭 [11]。下调靶向TGF-β的表达水平,可以减弱肿瘤细胞的侵袭能力,降低肿瘤恶性程度。

3. 酶

3.1. 异柠檬酸脱氢酶

异柠檬酸脱氢酶(isocitrate dehydrogenase, IDH)参与细胞中的能量代谢,可以催化异柠檬酸使其氧化为酮戊二酸 [14]。人体中的IDH分为三种,定位于不同的亚细胞室,发挥不同的生理功能。位于细胞质中的IDH1发挥过氧化物酶的作用,位于线粒体中的IDH2和IDH3参与三羧酸循环 [14],它们发挥作用需要不同的辅助因子,IDH1和IDH2依赖烟酰胺腺嘌呤二核苷磷酸(NADP+),IDH3则依赖烟酰胺腺嘌呤二核苷酸(NAD+)。世界卫生组织根据IDH的表型将其分为三类:IDH野生型、含1p/19q代号的IDH突变型,没有1p/19q代号的IDH突变型 [15]。IDH突变的胶质瘤和IDH没有突变的胶质瘤在分子水平表型相似,在生化水平上,IDH突变会引起代谢异常,最重要的代谢异常之一是合成代谢物2-羟基戊二酸(2-HG),2-HG的存在使得细胞向致癌性代谢转变 [16],其中IDH1/IDH2被认为是最早的遗传变异之一,对胶质瘤的发展起关键作用 [17]。临床前的体外实验中,IDH1突变后星形胶质细胞转变为永生化的细胞系,体内实验中,Beatrice Philip等人使用已建立的RCAS/TVA小鼠胶质瘤模型,使表达Nestin的细胞发生IDH1突变,促进了肿瘤的生成和发展 [18]。临床病例中,80%的患者分析结果显示存在IDH1/2突变 [19]。一项9例使用IDH1突变抑制剂DS-1001b (具有高血脑屏障通透性)的患者追踪观察发现,2名患者预后较好,7名患者病情稳定 [20]。在另一项29人的患者队列中,服用IDH1抑制剂vorasidenib后,1人完全缓解,3人症状减轻,10人病情稳定,并显著抑制了2-HG的产生 [20]。大量临床前和临床数据表明,初期抑制IDH突变可以延缓肿瘤形成,而在后期抑制其突变则使预后较差。

3.2. 基质金属蛋白酶

基质金属蛋白酶(Matrix metalloproteinase, MMP)需要Ca2+、Zn2+等金属离子辅助而发挥作用。目前 MMPs家族已鉴定分离出26个成员,在胶质瘤中起关键作用的主要有MMP2、MMP7和MMP9,作为其他通路下游的靶效应器抑制肿瘤细胞的发生发展过程。肺腺癌转录相关转移本1 (MALAT-1)可以抑制肿瘤的转移,研究发现MALAT-1发挥作用是通过降低MMP2的表达,减弱MMP2的活性从而抑制肿瘤细胞的侵袭和转移 [21]。H. WU等人通过qRT-PCR证明miR-93-5p在胶质瘤中低表达,而MMP2是miR-93-5p的直接靶标,当上调miR-93-5p时,MMP2表达下降,肿瘤细胞生长受到抑制 [22]。另一类microRNA,miR-2276则直接靶向MMP7,抑制MMP7上游的乳腺癌抗雌激素药物耐药性基因4 (BCAR4)可以调控miR-2276进而下调MMP7的表达,抑制肿瘤的侵袭 [23]。而MMP9可以在mRNA真核起始因子4A3 (eIF4A3)诱导下自身环化形成circMMP9并上调表达水平,circMMP9进一步靶向miR-124形成circMMP9/miR-124信号轴,上调miR-124促进肿瘤恶性程度增加 [24]。由于MMPs自身促转移的特性,靶向MMPs抑制其表达对于胶质瘤的治疗至关重要。

3.3. O6-甲基鸟嘌呤-DNA甲基转移酶

O6-甲基鸟嘌呤-DNA甲基转移酶(O6-methylguanine-DNA methyltransferase, MGMT)可以将烷基从鸟嘌呤转移到半胱氨酸残基上来修复受损的o6-甲基鸟嘌呤 [25]。MGMT是一种进化保守且普遍存在的酶,受多种机制调控,在胶质瘤中可以通过启动子甲基化沉默MGMT基因的表观遗传 [26]。替莫唑胺是目前临床上公认的治疗胶质瘤的化疗药物,MGMT甲基化调节MGMT在胶质瘤细胞中的表达,使得肿瘤细胞对替莫唑胺产生耐药性,减弱治疗效果,全身性的MGMT抑制剂副作用大,在临床应用中受到限制,研究发现胶质瘤中NF-κB的表达水平升高,抑制NF-κB下调了MGMT的表达,在体内外实验中均显著抑制了肿瘤的生长 [27]。此外β-catenin可以增加细胞中ROS的水平从而抑制MGMT的表达 [28]。除以上两条通路外,IFN-β可以用作增敏剂,通过诱导P53蛋白减弱MGMT的表达,增强胶质瘤细胞对替莫唑胺的敏感性而不产生全身性的副作用 [29]。因此,开发针对MGMT的增敏剂,增强肿瘤细胞对替莫唑胺的敏感性是目前治疗胶质瘤最有效的方法之一。

4. 信号通路

4.1. NF-κB

NF-κB是转录因子家族,由5种亚基组成:p65,p50,p52,RelB和c-Rel [27],可形成异二聚体或同二聚体,并与靶基因启动子区域的共有DNA序列结合 [30]。在大多数恶性肿瘤中,NF-κB均被高度激活,胶质瘤作为恶性肿瘤之一,NF-κB途径的激活尤其明显,因此研究胶质瘤中NF-κB通路对于治疗胶质瘤非常重要。慢病毒诱导的恶性神经胶质瘤小鼠模型及RNA-seq全基因组分析表明,抑制NF-κB的活性或靶向诱导NF-κB基因是治疗胶质瘤的一种有吸引力的治疗方法 [30]。Notch基因可以编码高度保守的细胞表面受体,Notch1作为胶质瘤的预后因子,在胶质瘤初始阶段被上调,针对Notch1的mRNA可以下调NF-κB,在体内外均促进细胞凋亡 [31]。由于存在血脑屏障,许多化疗药物不能进入颅内,使得临床前效果很好的药物难以发挥作用,而部分化疗药物可以促进NF-κB的活化,将同时增强细胞膜渗透性和抑制NF-κB的CB5005肽与聚乙二醇化脂质体偶联修饰,显著增加了神经胶质瘤细胞对脂质体的摄取,并大大提高了脂质体对肿瘤球体的渗透性 [32]。许多研究均表明,NF-κB是治疗胶质瘤的重要靶标。

4.2. PI3K/Akt

PI3K是胞内的磷脂酰肌醇3-激酶,可分为3类,研究最广泛的是第1类,由1个调节亚基和1个催化亚基组成,调节亚基具有SH2和SH3区域,可以和具有相关区域的靶蛋白结合发挥作用,催化亚基分为p110α、β、δ、γ四种。PI3K参与多种细胞活动,包括细胞增殖,代谢,迁移和血管生成 [33]。胶质瘤中的PI3K-AKT-mTOR信号通路经常被激活,通过建立基因工程构建的自发生成胶质瘤的小鼠模型,表明PI3K抑制剂和PI3K/mTOR双重抑制剂都具有抗肿瘤活性 [34]。PI3K抑制剂主要是通过延迟肿瘤发生,从而延长生存期。PI3K/mTOR双重抑制剂对U87原位瘤抑制效果增加,主要通过G1细胞周期停滞促进细胞凋亡,二者联用可使细胞中Bax和剪切型Caspase-3水平增高,Bcl-2的水平降低 [35]。除此之外,PI3K/Akt和JNK通路对于胶质瘤的生长,迁移和浸润也是至关重要的。由于PI3K有四种催化亚型,同时抑制四种不同的亚型和JNK时对胶质瘤的特性有不同的影响,只有PI3Kp110β同工型和JNK的联合抑制才具有协同作用,这可能是胶质瘤的有效和有前途的治疗方法 [33]。相比于单一抑制PI3K,联合抑制PI3K/mTOR所产生的协同作用大大增强了治疗效果,这可能是这一通路有效和有前途的治疗方法。

5. 免疫球蛋白

PD-1/PD-L1

PD-1 (programmed death 1)即程序性死亡受体1,是一种重要的免疫抑制分子,属于免疫球蛋白超家族,包含268个氨基酸残基。PD-L1 (Programmed cell death 1 ligand 1)即细胞程式死亡–配体1,是由CD274基因编码的蛋白质。在大多数肿瘤细胞中,作为免疫检查点,肿瘤细胞表面表达PD-L1,PD-L1通过结合T淋巴细胞上的PD-1从而抑制T淋巴细胞发挥免疫调节作用产生免疫逃避 [36] [37],抑制PD-1/PD-L1免疫检查点在肿瘤治疗中取得了显著效果 [38]。和许多肿瘤一样,PD-1/PD-L1在胶质瘤中高表达,一项96例胶质瘤患者体内PD-L1表达水平队列分析表明,69%的患者PD-L1阳性细胞数至少1%,31%的患者PD-L1阳性细胞数至少5%,而PD-1/PD-L1的表达水平与预后相关,表达水平越高则预后越差 [39]。另一项针对胶质瘤患者肿瘤组织中PD-1/PD-L1表达水平队列分析研究表明,新诊断的及复发性的胶质瘤患者中,70%以上的胶质瘤标本中含有不同程度的弥漫性/原纤维性PD-L1表达,而在新诊断的病例中这一比例更高 [40]。不同研究的临床数据均表明,PD-1/PD-L1在胶质瘤的进展和免疫治疗中有关键作用,它解决了化疗药物不易透过血脑屏障的难题,目前在胶质瘤治疗中,开发针对PD-1/PD-L1的抑制剂是一个有效策略,许多PD-1/PD-L1抑制剂已显示出良好治疗效果,如已上市的尼鲁单抗。但胶质瘤的免疫原性低,免疫细胞和细胞因子之间存在相互干扰,使得免疫抑制,因此多药联用就尤为重要。同时抑制PD-1/PD-L1和另一个新的免疫抑制点TIGIT,显著提高了胶质瘤小鼠的生存率 [41]。而在临床中,将PD-1作为辅助免疫疗法同样取得了显著效果,35名复发性胶质瘤患者中,有16名患者在手术治疗前使用了PD-1抑制剂作为辅助疗法,19名患者在手术后使用PD-1抑制剂,将PD-1抑制剂作为辅助疗法的16名患者生存期明显长于未使用者 [3]。PD-1/PD-L1抑制剂是最近研究的热点方向,它自身不受血脑屏障干扰也使得在临床应用中取得了良好的治疗效果。

6. 展望

胶质瘤成因复杂,仅仅单一抑制某个靶点或通路成效甚微,长时间使用甚至引起耐药性,因此开发多靶点或多通路同时抑制的药物是未来的研究方向。胶质瘤药物治疗的难题之一还在于脑部存在血脑屏障,许多药物无法透过进入脑内发挥作用,单抗类药物由于其特殊的性质,可以跨越血脑屏障,另外,将脂溶性好的小分子连接在化疗药物上,也是未来研究的热点。

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