修回日期: 2018-08-24
接受日期: 2018-09-06
在线出版日期: 2018-10-18
肝内胆管癌是一类相对少见的恶性肿瘤. 极其不良的预后源于对其分子发病机制认识不足和有效治疗方法的匮乏, 精准医疗计划的提出和癌症基因组学的研究, 有助于对肿瘤分子发病机制深入了解以及发现潜在治疗靶点. 随着基础和临床研究的深入, 精准靶向治疗将能够更好地改善患者预后, 提高总生存率.
核心提要: 肝内胆管癌(intrahepatic cholangiocarcinoma，iCCA)是一类相对少见的恶性肿瘤. 由于对于其分子发病机制认识不足并且缺乏有效的治疗方法, 肝内iCCA的预后欠佳. 但随着基础和临床研究的深入, 精准靶向治疗将能够更好地改善患者预后, 提高总生存率.
引文著录: 奚松阳, 房栋, 霍介格. 肝内胆管癌的分子靶向治疗进展. 世界华人消化杂志 2018; 26(29): 1707-1716
Revised: August 24, 2018
Accepted: September 6, 2018
Published online: October 18, 2018
Intrahepatic cholangiocarcinoma is an uncommon malignant tumor with a poor prognosis due to an incomplete understanding of its molecular pathogenesis and a lack of effective treatment. Precision medical planning and cancer genomics can help to understand the molecular pathogenesis of cancer and identify potential therapeutic targets. With the deepening of basic and clinical research, accurate targeted therapy will be able to improve the prognosis and overall survival of patients with intrahepatic cholangiocarcinoma.
- Citation: Xi SY, Fang D, Huo JG. Progress in molecular targeted therapy of intrahepatic cholangiocarcinoma. Shijie Huaren Xiaohua Zazhi 2018; 26(29): 1707-1716
- URL: https://www.wjgnet.com/1009-3079/full/v26/i29/1707.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v26.i29.1707
胆管癌(cholangiocarcinoma, CCA)是一种具有不同胆管细胞分化特征的上皮细胞恶性肿瘤. CCA根据解剖位置可分为肝内CCA(intrahepatic cholangiocarcinoma, iCCA), 肝门部CCA(perihilar cholangiocarcinoma, pCCA)和远端CCA(distal cholangiocarcinoma, dCCA). 每种亚型都有独特的流行病学, 生物学, 预后和临床治疗策略. 过去几十年来, 全球CCA尤其是iCCA的发病率有所增加[1]. iCCA在东亚更为常见, 在中国每10万人中有10人发病. iCCA约占所有CCA的10%, 它来自肝实质内的周围胆管, 靠近次级胆管根部. 组织学上, 大多数iCCA属于腺癌. 目前研究发现临床上只有15%患者存在手术切除的可能性, 并且中位生存期往往小于3年[2]. 对于晚期或不可切除的患者, 局部和全身化疗是主要的治疗选择, 但是疗效欠佳. 随着精准医疗计划的提出和大量癌症基因组学的研究, 对肿瘤分子发病机制的了解也不断深入, 发现了大量潜在治疗靶点, 目前国内外正在进行大量关于iCCA分子靶向治疗的临床试验, 这些研究也取得了较为可喜的成果. 本文就iCCA的分子靶向治疗进展作一阐述, 为进一步深入研究提供参考.
近年来, 随着二代测序等分子检测技术的日趋完善, 一些研究采用多组学方法对iCCA的基因谱及表达谱进行了分析, 如图1所示, 发现了大量相关的基因改变[3].
异柠檬酸脱氢酶(Isocitrate dehydrogenase, IDH)是参与细胞能量代谢的三羧酸循环中的限速酶, 催化异柠檬酸氧化脱羧转变为α-酮戊二酸(α-Ketoglutarate, α-KG). 针对中国103例ICC患者的肿瘤和对照样本的测序结果显示IDH1/2蛋白的基因热点突变率约占所有iCCA患者的10%-23%, 且相对肝外CCA具有高度特异性[4-6]. 目前研究发现IDH突变导致2-HG水平上调, 促使HIF1α活性增强, DNA及组蛋白处于高甲基化状态, 引起基因组高甲基化修饰的表观遗传改变和细胞的异常分化, 可能是导致iCCA发生发展的原因[7,8].
近年来, 越来越多的证据表明成纤维细胞生长因子受体(fibroblast growth factor receptor, FGFR)是某些癌症的驱动基因, 并且以"细胞自治"的方式维持肿瘤细胞的恶性特征, 通过诱导促有丝分裂和生存信号、促进肿瘤细胞侵袭转移、促进上皮间质转化、促进血管生成及参与肿瘤复发耐药作用作为癌基因参与肿瘤发生发展进程的多重步骤, 但也有研究证实FGFR信号通路在某些肿瘤类型中具有抑制肿瘤的功能[9,10]. Wu等[11]人在2013年率先报道FGFR在iCCA中的表达, 并发现2例FGFR2-BICC1蛋白的异常表达. Nakamura等[12]人对260个胆管癌 (biliary tract cancers, BTCs)患者进行了全面的基因组分析, 发现40%的病例具有靶向基因的改变, 其中FGFR2在iCCA呈现高表达.
表皮生长因子受体广泛分布于哺乳动物上皮细胞、成纤维细胞、胶质细胞、角质细胞等细胞表面, 对细胞的生长、增殖和分化等生理过程发挥重要的作用. 其在肿瘤细胞中呈现过度表达或过度活化, 可促进肿瘤细胞不断增殖, 逃避细胞凋亡, 促使肿瘤的血管生成. 表皮生长因子受体家族中与iCCA关系最为密切的是上皮生长因子受体(epidermal growth factor receptor, EGFR), 其在iCCA患者中的大多呈现过表达, 但突变一般较为罕见[13]. EGFR的活化可降低iCCA患者的总体生存, 并可提示其存在淋巴结转移的风险[14].
和许多其他癌症一样, RAS/RAF/MEK/MAPK通路在CCA中常常表达异常[15]. 该通路可通过与细胞周期调节蛋白(如p53, p16 INK4A, p21 CDKN2A)相互作用调控细胞周期[16], 干预 BCL-2信号传导来逃避细胞凋亡. KRAS不仅在RAS-RAF-MEK-MAPK通路中起着重要作用, 还能影响PI3K/AKT通路, 因此具有特别重要的意义. KRAS基因在iCCA中的突变率为8.6%-24.2%[3], 且其突变与神经浸润、分期晚、预后不良有关[17]. BRAF是KRAS的下游靶点, 也易在iCCA中呈现突变[3]. BRAF突变的频率显示出相当大的地理变异性, 在德国和希腊约有20%的胆管肿瘤患者携带这种突变[18,19], 而在台湾仅有不到1%[20], 甚至在智利为0%[21].
PI3K/AKT/mTOR通路几乎在一半的恶性肿瘤中表现出过度活性, 其中就包括iCCA[14]. 和RAS-RAF-MEK通路一样, 该通路受EGF、血管内皮生长因子(vascular endothelial growth factor, VEGF)和肝细胞生长因子及受体的影响. 该通路可通过激活BCL-2并阻断caspase-9活性, 保护肿瘤细胞免于凋亡. 该途径还能促进细胞周期的进展和血管生成[22], 还有研究发现PI3K/AKT/mTOR通路参与调节基质金属蛋白酶的产生, 这在局部侵袭中起着重要作用[14]. 对101例iCCA的研究显示p-AKT1和p-mTOR的异常表达均与良性预后相关[23].
Wnt/β-catenin通路参与了细胞侵袭和迁移的调控. 在15%iCCA的患者中, β-catenin呈现细胞核高表达细胞膜低表达[24]. Wnt通路激活与CCA异种移植肿瘤模型中的化疗耐药和转移扩散相关[25], 并且Wnt通路抑制剂可逆转细胞系中的化疗耐药[26]. 在泰国血吸虫相关CCA的突变全基因组测序研究中发现Wnt通路中RNF43基因存在9.3%的突变[27,28].
c-MET被认为是侵袭性生长的关键调节基因, HGF与其受体c-MET的相互作用激活其他通路的表达, 如MAPK, PI3K/AKT和STAT等[29]. MET在iCCA中呈4-7%过表达[3], 在一些研究中已经将MET的过度表达与EGFR家族成员的过表达联系在一起[30], 并且发现HGF在iCCA迁移和侵袭中起着重要作用[31].
研究发现在iCCA中存在Hedgehog通路相关基因的表达[32], 并且发现通过抑制Hedgehog通路在小鼠CCA异体移植瘤中的表达可抑制上皮间质转化和减少肿瘤体积[33], 表明这一通路可作为一个潜在的治疗新靶点.
炎症是iCCA发病机制中的关键因素之一. 炎性细胞因子IL-6由肿瘤细胞以自分泌或旁分泌方式响应炎症刺激而分泌, 并可影响相关癌基因的表达[13]. JAK/STAT信号的激活在iCCA占50%, 并可影响超过70%的iCCA炎症亚型[34]. IL-6与gp130受体的结合可触发受体二聚化, 导致gp130相关的JAK激酶(JAK1, JAK2和TYK2)的激活和随后的STAT3激活, 从而影响肿瘤坏死因子相关凋亡诱导配体(TRAIL)介导的细胞凋亡, 诱导细胞生长, 分化和增殖. 此外, IL-6还可增加端粒酶活性, 促进肿瘤逃避衰老, 并参与相关生长因子受体(包括EGFR)的甲基化模式, 以及参与let-7家族miRNA的表达[13].
近年来, 随着对iCCA分子病理机制认识的深入, 肿瘤生物靶向治疗发展迅速, 临床应用潜力巨大. 生物靶向治疗是针对iCCA的关键致癌靶点(抗原、受体或者基因片段), 在细胞分子水平上设计相应的治疗干预策略. 药物通过体液循环到达瘤区, 特异性结合致癌位点, 诱导肿瘤细胞坏死、凋亡或被免疫细胞吞噬, 同时不会波及肿瘤周围的正常组织细胞. 目前iCCA的分子靶向治疗的临床研究的开展大部分包含在BTCs中, 较少进行单独的开展, 所以在部分靶向药物临床研究的介绍中以BTCs为整体进行展开(表1).
| 靶点 | 药物 | 临床研究号 | 临床研究 |
| IDH基因 | AG120 | NCT02073994 | Ⅰ期 |
| 达沙替尼 | NCT02428855 | Ⅱ期 | |
| FGFR | BGJ-398 | NCT02150967 | Ⅱ期 |
| INCC54828 | NCT02924376 | Ⅱ期 | |
| BAY1163877 | NCT01976741 | Ⅰ期 | |
| TAS-120 | NCT02052778 | Ⅰ期 | |
| ARQ-077 | NCT01752920 | Ⅱ期 | |
| EGFR | 西妥昔单抗 | NCT00552149 | Ⅱ期 |
| 帕尼单抗 | NCT01308840 | Ⅱ期 | |
| 厄洛替尼 | NCT00832637 | Ⅱ期 | |
| NCT00987766 | Ⅰ期 | ||
| 拉帕替尼 | NCT00107536 | Ⅱ期 | |
| 阿法替尼 | NCT01679405 | Ⅰ期 | |
| RAS/RAF/MEK/MAPK通路 | 司美替尼 | NCT01242605 | Ⅰ期 |
| NCT00553332 | Ⅱ期 | ||
| NCT02151084 | Ⅱ期 | ||
| PI3K/AKT/mTOR通路 | MK-2206 | NCT01859182 | Ⅱ期 |
| NCT01425879 | Ⅱ期 | ||
| 依维莫司 | NCT00973713 | Ⅱ期 | |
| copanlisib | NCT02631590 | Ⅱ期 | |
| Wnt /β-catenin通路 | DKN-01 | NCT02375880 | Ⅰ期 |
| c-MET、VEGFR2 | 卡博替尼 | NCT01954745 | Ⅱ期 |
| HGF/c-MET通路 | merestinib | NCT02711553 | Ⅱ期 |
| 血管生成 | 贝伐单抗 | NCT00361231 | Ⅱ期 |
| NCT00142480 | Ⅱ期 | ||
| NCT00356889 | Ⅱ期 | ||
| 西地尼布 | NCT00939848 | Ⅱ期 | |
| 索拉非尼 | NCT00955721 | Ⅱ期 | |
| NCT01093222 | Ⅱ期 | ||
| NCT00661830 | Ⅱ期 | ||
| 厄洛替尼 | NCT01093222 | Ⅱ期 | |
| 舒尼替尼 | NCT01082809 | Ⅱ期 | |
| 凡德他尼 | NCT00753675 | Ⅱ期 | |
| 帕唑帕尼 | NCT01855724 | Ⅱ期 | |
| 瑞格菲尼 | NCT02053376 | Ⅱ期 | |
| NCT02115542 | Ⅱ期 | ||
| 雷莫芦单抗 | NCT02711553 | Ⅱ期 | |
| ALK和ROS1 | ceritinib | NCT02374489 | Ⅱ期 |
| Entrectinib | NCT02568267 | Ⅱ期 | |
| 间皮素 | Anetumab ravtansin | NCT03102320 | Ⅰ期 |
| CDK4/6 | ribociclib | NCT03065062 | Ⅰ期 |
| palbociclib | NCT02022982 | Ⅰ期 | |
| PARP | niraparib | NCT03207347 | Ⅱ期 |
在Ⅰ期试验中, AG120(IDH1抑制剂, Agios)在具有IDH1突变的晚期实体瘤患者中表现出良好的耐受性(NCT02073994), 未呈现剂量限制性毒性. 贫血是使用AG120最常见的3级不良事件(5%). 在20例晚期iCCA患者中, 1例(5%)获得部分缓解, 11例(55%)患者疾病稳定. 在所有对AG120有反应的患者中观察到循环2-HG水平从99%降至73%, Ki67染色从96%降低至22%[3]. 其他IDH1和IDH2抑制剂最近已进入临床试验(NCT02273739, NCT02381886, NCT02481154), 并正在招募患有iCCA的患者. 最近通过包括17种BTCs在内的一大组癌细胞系的高通量药物筛选的研究发现达沙替尼对于IDH突变的iCCA具有惊人疗效[35]. 此外, 达沙替尼对IDH突变异体种植瘤的治疗中表现出明显的细胞凋亡和肿瘤消退[3]. 达沙替尼在IDH突变型晚期iCCA患者中的试验正在进行中(NCT02428855).
最早报道在CCA中使用的FGFR抑制剂是BGJ-398(Infigratinib, Novartis), 其对FGFR2的半数最大抑制浓度(IC50)为1.4 mmol/L. 有34名一线化疗后FGFR异常的晚期CCA患者接受了BGJ-398Ⅱ期临床试验, 其中包括FGFR2融合28例, FGFR2突变2例, FGFR2扩增3例或FGFR3扩增1例(NCT02150967). 研究发现治疗的中位时间为188天, 客观缓解率为22%(全部8例部分缓解的患者均有FGFR2融合)[36]. 与用酪氨酸激酶抑制剂治疗的其他致癌基因引发的肿瘤一样, 获得性耐药限制了一些患者的反应耐受性. Goyal 等首次报道了3例接受BGJ398治疗的FGFR2融合阳性iCCA患者产生临床获得性FGFR抑制剂耐药[37]. 进一步研究发现FGFR2激酶结构域中的多克隆次级突变, 这其中就包括3例患者中都存在的FGFR2 V564F基因突变.
INCC54828(Incyte, NCT02924376)、BAY1163877(Bayer, NCT01976741)以及不可逆FGFR抑制剂TAS-120(Taiho, NCT02052778)等其他选择性FGFR抑制剂目前正处在包括iCCA在内的晚期实体瘤患者的早期阶段试验中[3]. 非选择性多TKIs也可针对FGFR靶点, 其中ponatinib和pazopanib已证明在对化疗产生耐药性的iCCA个别患者中表现出活性[38]. 第三种非选择性TKI ARQ-087(ARQULE, NCT0175920)目前正处在FGFR异常肿瘤包括FGFR2融合阳性的已治疗晚期iCCA患者的Ⅱ期试验中, 其可抑制RET、PDGFR、KIT、Src和FGFR1-3(FGFR2的IC50为0.68 mmol/L). 第一阶段/第二阶段初步试验数据表明用ARQ-087治疗的12例FGFR2融合阳性晚期iCCA患者中有3例有部分反应(疾病控制率为75%)[39]. 目前体外研究正在尝试研发可以克服耐药性的FGFR抑制剂为临床提供新的治疗策略.
目前几个化疗(化疗药物大部分为吉西他滨和奥沙利铂)联合靶向EGFR的单克隆抗体西妥昔单抗治疗BTCs的试验都处在Ⅱ期临床中[3]. 在一项30例的小规模研究中发现有高肿瘤缓解率(63%)[40], 虽然这个可喜的发现并未在随机Ⅱ期BINGO研究中得到证实, 但其与其他西妥昔单抗联合化疗的Ⅱ期临床研究结果一致[41].
在KRAS野生型晚期BTC患者接受帕尼单抗联合吉西他滨、卡培他滨和奥沙利铂(46例)[42], 吉西他滨和奥沙利铂(31例)[43]治疗的两项独立的Ⅱ期临床试验中, 均达到74%的6 mo PFS和45%的有效率. 但是在使用帕尼单抗联合吉西他滨和依立替康随机治疗BTC患者的Ⅱ期研究发现OS无差异(31名患者中有7名患有KRAS突变)[44]. 目前帕尼单抗联合吉西他滨和奥沙利铂的最大随机Ⅱ期研究(Vecti-BIL研究)显示85名随机患者的生存率无差异[45].
埃罗替尼在不同的研究中显示出不同的结果[3]. 在一项Ⅲ期临床研究中133名患者被随机分配接受吉西他滨和奥沙利铂化疗联合或不联合厄洛替尼, 当所有BTC患者一起分析时, PFS或OS没有差异. 然而, CCA患者似乎确实从化疗加用厄洛替尼后获益, 其中位PFS从3 mo上升至5.9 mo[46], 目前正在进行进一步的临床试验(NCT00832637、NCT00987766). 拉帕替尼目前在两个独立的Ⅱ期临床试验中疗效欠佳[3]. 曲妥珠单抗目前正在开展在胆囊癌中的Ⅱ期临床试验(NCT00478140), 在iCCA中的临床相关研究尚未开展. 阿法替尼已经在Ⅰ期临床试验中显示了在一名CCA患者中具有活性[47], 目前正在进行阿法替尼联合顺铂和吉西他滨治疗BTCs患者的Ⅰ期研究(NCT01679405).
司美替尼是MEK抑制剂, 其在治疗转移性CCA的Ⅱ期研究结果显示中位PFS为3.7 mo, 中位总生存期为9.8 mo[48]. 在随后的对晚期CCA的Ib期研究中, 司美替尼、吉西他滨和顺铂的联合治疗可使中位PFS达到6.4 mo[49]. BRAF突变也可发生于CCA(主要在iCCA中), 在8例BRAF V600基因突变CCA中, 口服BRAF抑制剂维罗非尼治疗, 有1例患者取得了疗效[50].
MK-2206是AKT的抑制剂, 在8例至少接受过一次全身治疗的晚期BTCs患者的Ⅱ期临床研究中取得的结果是令人失望, 中位数PFS为1.7 mo, 中位OS为3.5 mo[51]. 依维莫司一线Ⅱ期研究显示27例患者中有14例在12 wk内实现肿瘤控制; 其中两个实现部分缓解. 中位PFS为6.0 mo、中位OS为9.5 mo[3]. PI3K抑制剂copanlisib(BAY 80-6946)一线化疗联合吉西他滨和顺铂的Ⅱ期临床试验正在进行中(NCT02631590).
尽管目前正在开发多种Wnt通路抑制剂, 但是只有少数应用到BTCs中. Eads和他的同事们在BTCs治疗的Ⅰ期临床试验中探讨了经典Wnt/β-catenin通路抑制剂DKN-01联合吉西他滨和顺铂的疗法是安全的, 并且可能延长了疾病的稳定时间[52].
在晚期CCA患者的Ⅱ期试验中发现卡博替尼对c-MET(IC50 = 1.3 mmol/L)和VEGFR2(IC50 = 0.035 mmol/L)均有较强的活性[53]. 目前正在进行merestinib联合顺铂/吉西他滨一线药物的随机Ⅱ期研究(NCT02711553).
在贝伐单抗联合吉西他滨和奥沙利铂的晚期BTCsⅡ期临床试验中发现在两个治疗周期后FDG-PET扫描的标准化摄取值显著降低, 特别是在部分缓解或稳定患者中[54]. 然而, 其6 mo PFS为63%是低于70%的目标率的. 贝伐单抗联合厄洛替尼在12%的患者中获得部分疗效, 51%的患者病情稳定, 中位OS为9.9 mo, 值得注意的是这个方案并没有同步化疗[55].
在随机Ⅱ期安慰剂对照ABC-03研究中, 我们观察到接受顺铂/吉西他滨联合西地尼布组与安慰剂组相比有效率从19%提升到44%, 并且6 mo PFS从61.3%上升至70.5%. 但是该研究并未改善中位PFS, 其原因可能与西地尼布耐受性相对较差相关[56].
其他TKIs抑制VEGF效果不佳. 在索拉非尼单药治疗[57,58]或联合厄洛替尼[59]或顺铂/吉西他滨[60]的Ⅱ临床研究中均未能发现其在BTCs中表现出足够的活性. 最近, 在随机的Ⅱ期安慰剂对照临床研究中索拉非尼吉联合西他滨后并未能改善PFS[61]. 包括56例BTCs患者在内的舒尼替尼Ⅱ期临床试验报告指出中位疾病进展时间仅为1.7 mo, 客观缓解率为8.9%, 疾病控制率为50%[62]. 在173例患者中探索凡德他尼的作用的VanGogh研究中未能显示PFS的改善[63]. 帕唑帕尼(NCT01855724), 瑞格菲尼(NCT02053376, NCT02115542)和雷莫芦单抗(NCT02711553)的临床研究尚在进行中.
研究发现在iCCA患者中检测到涉及ROS1相关激酶ALK(EML4-ALK)的基因融合[64]. ALK和ROS1抑制剂ceritinib目前正在接受应用于ROS1阳性或ALK阳性晚期pCCA或iCCA(NCT02374489)Ⅱ期临床试验评估. Entrectinib是一种选择性酪氨酸激酶抑制剂, 具有抗ROS1和ALK(以及TRKA, TRKB和TRKC)的活性, 目前正处在涉及晚期ROS1或ALK融合的实体肿瘤患者的Ⅱ期临床研究中(NCT02568267), 其中也包括CCA在内.
间皮素是一种在非恶性间皮细胞中表达的细胞表面蛋白, 常在CCA中异常表达, 并与晚期和转移性疾病、不良的总生存期有关[65]. 因此, 这种蛋白质是治疗的潜在靶点. Anetumab ravtansine是一种抗间皮素抗体-药物结合物, 正处在招募患有异常间皮素表达的晚期CCA患者的Ⅰ期临床试验中进行试验中(NCT03102320).
CDKN2A是编码细胞周期进展的必要负调节p16INK4A和p14ARF蛋白的基因, 它在CCA中往往呈现丢失状态[12,66,67]. 这些研究显示CDK4/6抑制剂, 如ribociclib和palbociclib在治疗CCA的潜力. 这些药物目前已批准用于治疗乳腺癌, 并且正在进行一系列其他包括CCA在内的实体器官恶性肿瘤的临床试验(NCT03065062, NCT02022982).
目前研究发现肿瘤抑制基因BRCA1和BRCA2在CCA中存在突变[12,68]. BRCA突变的肿瘤通常对聚ADP核糖聚合酶(poly ADP-ribose polymerase, PARP)抑制敏感. 在18例BRCA突变CCA患者的回顾性临床分析中发现接受PARP抑制剂治疗的四名患者中有一名患者保持持续的治疗反应, PFS持续时间为42.6 mo[69]. PARP抑制剂niraparib的包括CCA在内的晚期恶性肿瘤患者Ⅱ期试验正在进行中(NCT03207347).
iCCA虽是少发的恶性肿瘤, 但早期诊断率低, 恶性程度高, 病程进展快、手术切除率低及复发率高, 预后不佳. 目前的外科治疗主要关注在根治性切除. 由于iCCA复发率高, 为取得较好的治疗效果, 外科医生不得不一再扩大手术切除范围, 而切除范围的扩大虽延长了患者的生存时间, 但也由于削减肝功能储备的原因带来了更高的手术后并发症及手术死亡率. 目前全身性的治疗中, 可选择的方案有限, 疗效也欠佳, 且多数患者因处于晚期而无法进行化疗. 分子靶向治疗给我们带来了新的思路, 由于iCCA的形成、生长、侵袭和转移等过程由多种分子和信号转导通路参与和调控, 因而针对iCCA的靶向治疗有多种可选择的靶点, 而目前有大量相关基础研究和临床试验正在进行中, 其中部分研究已显示了较好的苗头.
尽管目前在iCCA分子机制方面的研究取得了相当大的进展, 但仍有大量的工作需要我们进一步完善. 对于正常胆管上皮细胞向侵袭性恶性肿瘤的分子改变和转化的因果关系目前尚未研究透彻. 对于产生癌细胞表型的各种信号传导途径和组分之间的相互作用我们仍不完全了解. 这些复杂的相互作用可能是加深我们对癌症异质性基础的理解和预测个体肿瘤对特定治疗的易感性的关键. 目前靶向治疗iCCA临床研究的数据和结论多来自于单臂的Ⅱ期临床试验, Ⅲ期临床研究尚无成熟的确定性结果, 仍有待于多中心、大样本、随机对照试验进一步证实靶向治疗药物的有效性与安全性.
随着大数据时代和二代测序等生物技术的发展, 与患者分子生物病理学、基因表达特征相匹配的个体化诊断和治疗将成为可能, 精准靶向治疗将大大改善iCCA患者预后, 提高总生存率.
学科分类: 胃肠病学和肝病学
手稿来源地: 江苏省
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编辑:崔丽君 电编:张砚梁
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