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通讯作者:

焦作义(1977-),男,甘肃天水人,博士生导师,从事肝胆胰胃外科、腹腔镜外科和肝移植。E-mail:jiaozuoyi@163.com

中图分类号:R730

文献标识码:A

文章编号:2096-8965(2020)01-0050-06

DOI:10.12287/j.issn.2096-8965.20200108

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目录contents

    摘要

    建立合适的临床前研究模型是肿瘤研究转化的关键。目前,抗肿瘤药物的研究发展迅速,但由于缺乏合适的临床前期研究模型,大部分药物在进入Ⅱ期临床试验前便夭折。人源性肿瘤异种移植模型 (Patient-derived Tumor Xenograft Model,PDX) 是将患者肿瘤组织直接接种于免疫缺陷小鼠而建立的新型肿瘤研究模型,该模型保留了其供体肿瘤的主要组织学和遗传学特征,能够在后续传代中保持稳定,是一种能与临床样本保持较高一致性,且具有高临床预测价值的临床前研究模型。PDX模型可用于临床前药物评估、生物标志物鉴定和个性化精准医疗研究领域。本综述归纳了PDX模型的建立方法、PDX模型的优势及其在肿瘤研究方面的应用和局限性,并对PDX模型的未来发展方向进行了展望。

    Abstract

    Establishment of appropriate preclinical research models is important for the tumor transformation research. Although the development of new anti-tumor drugs is emergent, but most of drugs are failed in phase Ⅱ clinical trials due to the limitations of preclinical research models. Patient-derived tumor xenograft (PDX) is one of the novel tumor research models established by inoculating patient tumors tissue directly into immunodeficient mice. PDX is a preclinical research model with high clinical predictive value due to its high conservatism of histological and genetic characteristics with donor tumors. Generally, PDX models are widely used in preclinical drug evaluation, biomarker identification and personalized medical treatment. In this review, the methods of PDX model establishment, the advantages, the applications and the limitations of PDX model in tumor clinical research are summarized. At last, we prospect the future development of PDX model in tumor related research.

  • 前言

  • 临床前期模型在人类抗肿瘤药物的开发研究中至关重要。在过去的半个世纪,传统细胞系模型(以NCI-60 为代表) 是最常用的人类肿瘤研究模型[1],但该模型与人体肿瘤微环境的区别较大,导致其在临床试验中预测价值较低。传统肿瘤细胞系在传代过程中,细胞特性发生极大改变,例如遗传信息的插入与丢失、生长和侵袭特性的改变以及特定细胞群的丢失[2, 3],而肿瘤组织是由不同特征的高度异质性亚群的癌细胞组成,且肿瘤微环境在肿瘤的发生、发展过程中不可或缺,因此,在临床研究中,细胞系肿瘤研究模型无法代表复杂的肿瘤异质性[4]。基于以上原因,传统细胞系肿瘤研究模型无法满足临床肿瘤模型研究的需要,尤其是在肿瘤研究转化的需要方面。

  • 科研人员一直致力于开发和建立新的、具有代表性的肿瘤研究模型,PDX模型是最具潜力的模型之一,被广泛应用于经典化疗药物和新药的临床前研究。研究表明,临床患者对细胞毒性药物的反应与PDX模型的结果高度一致[5],同时,相较于基因敲除小鼠,PDX模型肿瘤异质性高,建模时间短, 接近人体肿瘤微环境,故该模型已经逐渐成为首选的临床前研究工具[6, 7]。本综述概述了PDX模型的建立方法,PDX模型在肿瘤研究中的优势、应用及局限性,并对PDX模型未来的发展进行了展望。

  • 1 PDX模型的建立方法

  • 目前已有研究对PDX模型的建立方法进行了全面的总结[8],虽然建模方法众多,但建模流程相同。图1为PDX模型的建立流程。该模型的建立过程中,首先通过手术或活检获取肿瘤组织,其来源可为原发性或转移性实体瘤,或使用恶性胸水或腹水作为种植肿瘤来源;接着,以碎片或单细胞悬液的形式将肿瘤植入小鼠,通常选择小鼠腋下、背部、 肾包膜处及原位作为肿瘤植入部位,植入前常与基质胶或人成纤维细胞及间质干细胞混合,对于激素敏感的肿瘤,种植后使用激素以提高PDX模型的成功率。建模成功后,待肿瘤长至直径约1~2 cm时,可将肿瘤从第一代宿主(P0) 剥离,一部分组织切碎至3 mm×3 mm×3 mm左右,植入新的小鼠(P1),一部分用多聚甲醛固定保存以后继续检测, 或用冻存液保存以复苏保种传代。以此类推,可繁育足够数量的PDX小鼠后代(P2,P3,…)。目前,移植宿主主要选择裸鼠、SCID小鼠、NODSCID小鼠、NSG小鼠(在NOD-SCID基础上敲除IL2 受体)、日本的NOG小鼠、BRG小鼠等[9],其中,依据肿瘤植入指数(Tumor Engraftment Index, TEI) 这一公认的定量评估小鼠免疫缺陷程度的评分标准[10],得出NSG小鼠是目前最优的PDX模型移植宿主。

  • 图1 建立PDX模型的流程示意图

  • 研究人员在方法建立的过程中,对肿瘤的来源和接种位置与移植成功率的关系进行了研究,结果得出,转移灶肿瘤组织来源比原发灶肿瘤组织来源构筑的PDX模型具有更高的成功率[11, 12]。在接种位置对移植成功率的影响研究中,研究人员得出结论,由于供血量不同,肾包膜植入比皮下植入具有更高的移植成功率,在非小细胞肺癌移植中成功率高达90%[13, 14]

  • 综上,研究人员已经提出了多种PDX模型的建立方法,优化了PDX模型中出现的各种问题, 但仍无法满足临床前肿瘤研究的需求,因此,开发新的PDX模型建立方法仍是PDX模型建立及应用的主要工作之一。

  • 2 PDX模型的优势

  • PDX模型的优势主要体现在两方面:第一, PDX模型保留了供体肿瘤的生物学特征、大体的组织结构和超微结构等关键特征,且能够在连续传代中保持一致。同时,基因分析结果显示,供体肿瘤与其PDX之间无显著的DNA结构重排积累[15],且不同传代(多达10 代) 的PDX模型对药物治疗反应率相同,说明PDX模型的基因表达具有很高的稳定性[16, 17],仅存在传代中人肿瘤基质逐渐被小鼠基质所取代,导致模型中涉及肿瘤基质和免疫功能的基因表达减少的问题。第二,PDX模型的临床预测价值较高。由于PDX模型和临床观察结论有较高的一致性,其在药效评价[8]、生物标志物的筛选[18] 和预测患者对药物响应程度[19-21] 中具有重要的作用。因此,越来越多的研究人员对PDX模型在肿瘤研究中相关的应用进行了开发。

  • 3 PDX模型在肿瘤研究中的应用

  • 3.1 药物的开发及生物标志物的检测

  • 由于缺乏高预测价值的临床前研究模型及合适的生物标志物筛选,导致大量进入Ⅱ期临床试验的药物无法进行后续临床研究[22, 23]。因此,具有高临床预测价值的PDX模型在生物标志物的筛选及药物开发中可为临床前Ⅱ期研究及后续试验提供强有力的支持。

  • 研究表明,肿瘤靶向药物及细胞毒性药物,在PDX模型中的药物反应率与临床检测到的药物反应率相似。如PDX模型中,EGFR抑制剂(西妥昔单抗)对结直肠癌(Colorectal Cancer,CRC)的肿瘤缓解率达到了10.6%,与临床检测到的结肠癌患者的肿瘤缓解率接近[23];同样地,PDX模型在头颈部鳞状细胞癌(Squamous Cell Carcinoma of the Head and Neck,SCCHN)患者的肿瘤缓解率中展现出很好的一致性[24]。另外,在KRAS突变的CRC的PDX模型研究中,MEK和PI3K/mTOR抑制剂治疗效果差,与 Ⅰ期的临床检测数据一致[25]。同时,利用PDX模型的胰腺导管腺癌(Pancreatic Ductal Adenocarcinoma, PDAC)的前瞻性研究中发现联合用药(紫杉醇和吉西他滨) 对肿瘤治疗有效,该结果也与联合方案在临床中的疗效相同,与此同时,在一项随机Ⅲ期研究中,该方案已证实可以延长晚期PDAC患者的生存时间[26]。综上,PDX模型已经成为新的筛选临床前抗肿瘤药物的重要模型。

  • 此外,PDX模型在筛选抗肿瘤药物的同时,还可识别潜在的生物标志物。在CRC的研究中,明确表明KRAS突变的PDX模型对西妥昔单抗无效,无KRAS突变是其治疗CRC的临床生物标志物[27, 28]。 而在PDAC的PDX模型中发现,去氧胞苷激酶是吉西他滨药物疗效的预测因子,并得到了临床检测结果的证实[29, 30]

  • 耐药生物标志物的发现对于临床联合治疗方案至关重要。在CRC中,EGFR抑制剂耐药的肿瘤有相关的基因扩增,如人表皮生长因子受体2(Human Epidermal Growth Factor Receptor 2,HER2)和间质表皮转化因子(Mesenchymal to Epithelial Transition Factor,MET),因此,针对HER2 和MET基因的双靶点联合用药展现出了良好的疗效。同样,在SCCHN中,PIK3CA基因的突变激活会导致EGFR抑制剂药物的耐药,而与PIK3 抑制剂的联合用药可改善耐药[31]。如上,通过PDX模型,不仅可以探明抗肿瘤药物耐药机制,同时可验证联合用药的治疗方案,克服临床耐药的问题[32]

  • 3.2 联合临床试验

  • 药物进入临床试验阶段,由于临床试验的固有性质,即患者根据具体标准每次只能接受一种药物或治疗方案,导致缺乏足够有用的药物开发相关的信息,限制了在临床研究中药物的开发。同时,单一的药物或治疗方案,也容易导致患者出现极端反应或快速耐药,因此详细研究药物相关的潜在机制对患者的治疗意义重大。

  • 为解决患者耐药对肿瘤治疗效果的影响,联合临床试验应运而生。最初的形式是使用基因工程鼠(Genetically Engineered Mouse,GEM) 模型探索治疗方案的耐药机制[33],基于相同的模式,PDX模型同样被用于临床试验中开展联合研究,且成效显著[34, 35],图2 为具体流程从参与临床试验的患者发展而来的个性化PDX模型,使用相同的药物来模拟临床反应,该试验能够在患者和小鼠模型中同时评估药物反应,为研究敏感和耐药的生物标志物以及为克服耐药提供了有力的措施。

  • 3.3 精准医疗

  • 近年来,肿瘤学相关研究领域发展迅速,针对个体化治疗的精准治疗为肿瘤治疗带来了重大进展,但仍任重道远。一方面,部分患者很难检测到具有药物疗效的生物标志物,从而无法接受个性化的治疗方案;另一方面,随着肿瘤生物分子图谱的完善,部分患者中能够检测到多个潜在的治疗靶点,但很难得出最优的治疗方案。

  • 如上文所述,目前大量研究证明PDX模型中的药物反应与临床反应间存在显著相关性,因此, 联合PDX模型进行精准医疗将有利于克服如上精准医疗中存在的问题。以非小细胞肺癌(Non-small Cell Lung Cancer,NSCLC)为例,PDX模型的研究结果显示,约三分之二的NSCLC患者对一线化疗药物敏感,三分之一的患者出现耐药,但患者对敏感及抵抗的药物各不相同,表明基于患者的个体差异,肿瘤治疗需要个体化的精准医疗方案[36]。在图3中,我们描述了精准医疗中PDX模型的作用。

  • 图2 结合PDX小鼠模型的联合临床试验

  • 图3 结合PDX小鼠模型的个体化精准医疗决策

  • 4 PDX模型的局限性

  • 虽然PDX模型在肿瘤研究中扮演着越来越重要的角色,但其在肿瘤转化及应用的相关研究中, 仍存在一些局限性。在技术性方面的局限性主要包括:(1) 建立PDX模型的肿瘤组织如何获取和处理的问题。大块的肿瘤组织对于PDX建立有益, 但较小的样本,如肿瘤活检或细针穿刺更适合个性化的医学应用;(2) 不同类型的肿瘤存在不同的最佳移植部位;(3) PDX模型建立的时间与患者治疗时间的匹配性。建立PDX模型通常需要4-8个月的时间,而很多患者治疗窗比较短;(4) PDX模型较低的构建成功率无法满足部分肿瘤治疗的要求。对于某些具有特定表型的肿瘤类型,如激素受体阳性的乳腺癌,移植成功率很低,而实现肿瘤患者的精准医疗,必须将PDX模型成功率提高至60%~70%以上[37]。PDX研究的另一个局限在于, 该模型与正常人类肿瘤生长的真实情况略有差异, 如缺乏免疫系统及肿瘤微环境,且人肿瘤间质逐渐被小鼠间质组织替代。因此,PDX模型在筛选免疫介导剂如疫苗、免疫调节剂(如抗PD1) 或通过激活免疫成分(如抗CD40抗体) 作用方面的应用大大受阻[38]

  • 此外,研究发现建立PDX模型的过程对肿瘤具有选择性,PDX模型并不适用于所有肿瘤类型, 不同肿瘤类型PDX建模的难易程度差异较大。

  • 综上,针对PDX模型在肿瘤研究中存在的不足,克服如上的局限性成为提高其在肿瘤研究转化应用中发挥重要作用的一个方向。

  • 5 展望

  • 目前PDX模型在肿瘤研究领域成效显著,但并未在临床相关研究中得到普遍应用,缺乏实质性突破。肿瘤组织种植程序的改进,免疫缺陷小鼠的选择,PDX评估体系的完善,生物标志物的鉴定, 建模方法的改进等都是PDX相关研究未来发展的重要方向。

  • 其中,利用供体重建小鼠免疫系统,或开发出保留人类肿瘤基质不被小鼠基质所取代的PDX模型,是提高PDX模型在肿瘤研究中广泛应用的潜在发展方向[39]。目前更优的PDX小鼠模型建立方法,需要采用供体骨髓造血干细胞重建免疫系统, 高度模拟人类肿瘤发生、发展的过程。但是,骨髓造血干细胞不能完全构建和恢复人类正常的免疫系统谱,故而免疫系统重建在技术上仍困难重重。相信在不久的将来,随着3D培养技术及其他相关技术的改进,通过各团队的协力合作,PDX模型将有可能解决这一难题,探索出更优的临床前研究模型。

  • 参考文献

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    • [2] GILLET J P,CALCAGNO A M,VARMA S,et al.Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistance[J].Proc Natl Acad Sci USA,2011,108(46):18708-18713.

    • [3] HAUSSER H J,BRENNER R E.Phenotypic instability of Saos-2 cells in long-term culture[J].Biochem Biophys Res Commun,2005,333(1):216-222.

    • [4] JUNG J,LEE C H,SEOL H S,et al.Generation and molecular characterization of pancreatic cancer patientderived xenografts reveals their heterologous nature[J].Oncotarget,2016,7(38):62533-62546.

    • [5] FIEBIG H H,NEUMANN H A,HENSS H,et al.Development of three human small cell lung cancer models in nude mice[J].Recent Results Cancer Res,1985,97:77-86.

    • [6] CALLES A,RUBIO-VIQUEIRA B,HIDALGO M.Primary human non-small cell lung and pancreatic tumorgraft models-utility and applications in drug discovery and tumor biology[J].Curr Protoc Pharmacol,2013,61(1):14-26.

    • [7] TENTLER J J,TAN A C,WEEKES C D,et al.Patientderived tumour xenografts as models for oncology drug development[J].Nat Rev Clin Oncol,2012,9(6):338-350.

    • [8] HIDALGO M,AMANT F,BIANKIN A V,et al.Patientderived xenograft models:an emerging platform for translational cancer research[J].Cancer Discov,2014,4(9):998-1013.

    • [9] ITO M,HIRAMATSU H,KOBAYASHI K,et al.NOD/SCID/gamma(c)(null)mouse:an excellent recipient mouse model for engraftment of human cells[J].Blood,2002,100(9):3175-3182.

    • [10] YE W,JIANG Z,LI G X,et al.Quantitative evaluation of the immunodeficiency of a mouse strain by tumor engraftments[J].J Hematol Oncol,2015,8:59.

    • [11] NEMATI F,SASTRE-GARAU X,LAURENT C,et al.Establishment and characterization of a panel of human uveal melanoma xenografts derived from primary and/or metastatic tumors[J].Clin Cancer Res,2010,16(8):2352-2362.

    • [12] SIVANAND S,PENA-LLOPIS S,ZHAO H,et al.A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma[J].Sci Transl Med,2012,4(137):137r-175r.

    • [13] DONG X,GUAN J,ENGLISH J C,et al.Patient-derived first generation xenografts of non-small cell lung cancers:promising tools for predicting drug responses for personalized chemotherapy[J].Clin Cancer Res,2010,16(5):1442-1451.

    • [14] FICHTNER I,ROLFF J,SOONG R,et al.Establishment of patient-derived non-small cell lung cancer xenografts as models for the identification of predictive biomarkers[J].Clin Cancer Res,2008,14(20):6456-6468.

    • [15] LI S,SHEN D,SHAO J,et al.Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts[J].Cell Rep,2013,4(6):1116-1130.

    • [16] KEYSAR S B,ASTLING D P,ANDERSON R T,et al.A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics indefined molecular bins[J].Mol Oncol,2013,7(4):776-790.

    • [17] RUBIO-VIQUEIRA B,JIMENO A,CUSATIS G,et al.An in vivo platform for translational drug development in pancreatic cancer[J].Clin Cancer Res,2006,12(15):4652-4661.

    • [18] BERTOTTI A,MIGLIARDI G,GALIMI F,et al.A molecularly annotated platform of patient-derived xenografts("xenopatients")identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer[J].Cancer Discov,2011,1(6):508-523.

    • [19] ZHANG X,CLAERHOUT S,PRAT A,et al.A renewable tissue resource of phenotypically stable,biologically and ethnically diverse,patient-derived human breast cancer xenograft models[J].Cancer Res,2013,73(15):4885-4897.

    • [20] FICHTNER I,ROLFF J,SOONG R,et al.Establishment of patient-derived non-small cell lung cancer xenografts as models for the identification of predictive biomarkers[J].Clin Cancer Res,2008,14(20):6456-6468.

    • [21] MARANGONI E,VINCENT-SALOMON A,AUGER N,et al.A new model of patient tumor-derived breast cancer xenografts for preclinical assays[J].Clin Cancer Res,2007,13(13):3989-3998.

    • [22] WEI B R,HOOVER S B,PEER C J,et al.Efficacy,tolerability and pharmacokinetics of combined targeted MEK and dual mTORC1/2 inhibition in a preclinical model of mucosal melanoma[J].Mol Cancer Ther,2020,19(11):2308-2319.

    • [23] DANIEL V C,MARCHIONNI L,HIERMAN J S,et al.A primary xenograft model of small-cell lung cancer reveals irreversible changes in gene expression imposed by culture in vitro[J].Cancer Res,2009,69(8):3364-3373.

    • [24] KEYSAR S B,ASTLING D P,ANDERSON R T,et al.A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in de-fined molecular bins[J].Mol Oncol,2013,7(4):776-790.

    • [25] MIGLIARDI G,SASSI F,TORTI D,et al.Inhibition of MEK and PI3K/mTOR suppresses tumor growth but does not cause tumor regression in patient-derived xenografts of RAS-mutant colorectal carcinomas[J].Clin Cancer Res,2012,18(9):2515-2525.

    • [26] VON HOFF D D,ERVIN T,ARENA F P,et al.Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine[J].N Engl J Med,2013,369(18):1691-1703.

    • [27] BERTOTTI A,MIGLIARDI G,GALIMI F,et al.A molecularly annotated platform of patient-derived xenografts("xenopatients")identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer[J].Cancer Discovery,2011,1(6):508-523.

    • [28] JULIEN S,MERINO-TRIGO A,LACROIX L,et al.Characterization of a large panel of patient-derived tumor xenografts representing the clinical heterogeneity of human colorectal cancer[J].Clin Cancer Res,2012,18(19):5314-5328.

    • [29] SEBASTIANI V,RICCI F,RUBIO-VIQUEIRA B,et al.Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer:relationship to molecular mechanisms of gemcitabine resistance and survival[J].Clin Cancer Res,2006,12(8):2492-2497.

    • [30] RUBIO-VIQUEIRA B,JIMENO A,CUSATIS G,et al.An in vivo platform for translational drug development in pancreatic cancer[J].Clin Cancer Res,2006,12(15):4652-4661.

    • [31] KEYSAR S B,ASTLING D P,ANDERSON R T,et al.A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in defined molecular bins[J].Mol Oncol,2013,7(4):776-790.

    • [32] DAS T M,SALANGSANG F,LANDMAN A S,et al.Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance[J].Nature,2013,494(7436):251-255.

    • [33] CHEN Z,CHENG K,WALTON Z,et al.A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response[J].Nature,2012,483(7391):613-617.

    • [34] DING N,CUI X X,GAO Z,et al.A triple combination of atorvastatin,celecoxib and tipifarnib strongly inhibits pancreatic cancer cells and xenograft pancreatic tumors[J].Int J Oncol,2014,44(6):2139-2145.

    • [35] GARRIDO-LAGUNA I,TAN A C,USON M,et al.Integrated preclinical and clinical development of mTOR inhibitors in pancreatic cancer[J].Br J Cancer,2010,103(5):649-655.

    • [36] DONG X,GUAN J,ENGLISH J C,et al.Patient-derived first generation xenografts of non-small cell lung cancers:promising tools for predicting drug responses for personalized chemotherapy[J].Clin Cancer Res,2010,16(5):1442-1451.

    • [37] MURAYAMA T,GOTOH N.Patient-derived xenograft models of breast cancer and their application[J].Cells,2019,8(6):621.

    • [38] JUNTTILA M R,DE SAUVAGE F J.Influence of tumor micro-environment heterogeneity on therapeutic response[J].Nature,2013,501(7467):346-354.

    • [39] KALSCHEUER H,DANZL N,ONOE T,et al.A model for personalized in vivo analysis of human immune responsiveness[J].Sci Transl Med,2012,4(125):125r-130r.

  • 参考文献

    • [1] ABAAN O D,POLLEY E C,DAVIS S R,et al.The exomes of the NCI-60 panel:a genomic resource for cancer biology and systems pharmacology[J].Cancer Res,2013,73(14):4372-4382.

    • [2] GILLET J P,CALCAGNO A M,VARMA S,et al.Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistance[J].Proc Natl Acad Sci USA,2011,108(46):18708-18713.

    • [3] HAUSSER H J,BRENNER R E.Phenotypic instability of Saos-2 cells in long-term culture[J].Biochem Biophys Res Commun,2005,333(1):216-222.

    • [4] JUNG J,LEE C H,SEOL H S,et al.Generation and molecular characterization of pancreatic cancer patientderived xenografts reveals their heterologous nature[J].Oncotarget,2016,7(38):62533-62546.

    • [5] FIEBIG H H,NEUMANN H A,HENSS H,et al.Development of three human small cell lung cancer models in nude mice[J].Recent Results Cancer Res,1985,97:77-86.

    • [6] CALLES A,RUBIO-VIQUEIRA B,HIDALGO M.Primary human non-small cell lung and pancreatic tumorgraft models-utility and applications in drug discovery and tumor biology[J].Curr Protoc Pharmacol,2013,61(1):14-26.

    • [7] TENTLER J J,TAN A C,WEEKES C D,et al.Patientderived tumour xenografts as models for oncology drug development[J].Nat Rev Clin Oncol,2012,9(6):338-350.

    • [8] HIDALGO M,AMANT F,BIANKIN A V,et al.Patientderived xenograft models:an emerging platform for translational cancer research[J].Cancer Discov,2014,4(9):998-1013.

    • [9] ITO M,HIRAMATSU H,KOBAYASHI K,et al.NOD/SCID/gamma(c)(null)mouse:an excellent recipient mouse model for engraftment of human cells[J].Blood,2002,100(9):3175-3182.

    • [10] YE W,JIANG Z,LI G X,et al.Quantitative evaluation of the immunodeficiency of a mouse strain by tumor engraftments[J].J Hematol Oncol,2015,8:59.

    • [11] NEMATI F,SASTRE-GARAU X,LAURENT C,et al.Establishment and characterization of a panel of human uveal melanoma xenografts derived from primary and/or metastatic tumors[J].Clin Cancer Res,2010,16(8):2352-2362.

    • [12] SIVANAND S,PENA-LLOPIS S,ZHAO H,et al.A validated tumorgraft model reveals activity of dovitinib against renal cell carcinoma[J].Sci Transl Med,2012,4(137):137r-175r.

    • [13] DONG X,GUAN J,ENGLISH J C,et al.Patient-derived first generation xenografts of non-small cell lung cancers:promising tools for predicting drug responses for personalized chemotherapy[J].Clin Cancer Res,2010,16(5):1442-1451.

    • [14] FICHTNER I,ROLFF J,SOONG R,et al.Establishment of patient-derived non-small cell lung cancer xenografts as models for the identification of predictive biomarkers[J].Clin Cancer Res,2008,14(20):6456-6468.

    • [15] LI S,SHEN D,SHAO J,et al.Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts[J].Cell Rep,2013,4(6):1116-1130.

    • [16] KEYSAR S B,ASTLING D P,ANDERSON R T,et al.A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics indefined molecular bins[J].Mol Oncol,2013,7(4):776-790.

    • [17] RUBIO-VIQUEIRA B,JIMENO A,CUSATIS G,et al.An in vivo platform for translational drug development in pancreatic cancer[J].Clin Cancer Res,2006,12(15):4652-4661.

    • [18] BERTOTTI A,MIGLIARDI G,GALIMI F,et al.A molecularly annotated platform of patient-derived xenografts("xenopatients")identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer[J].Cancer Discov,2011,1(6):508-523.

    • [19] ZHANG X,CLAERHOUT S,PRAT A,et al.A renewable tissue resource of phenotypically stable,biologically and ethnically diverse,patient-derived human breast cancer xenograft models[J].Cancer Res,2013,73(15):4885-4897.

    • [20] FICHTNER I,ROLFF J,SOONG R,et al.Establishment of patient-derived non-small cell lung cancer xenografts as models for the identification of predictive biomarkers[J].Clin Cancer Res,2008,14(20):6456-6468.

    • [21] MARANGONI E,VINCENT-SALOMON A,AUGER N,et al.A new model of patient tumor-derived breast cancer xenografts for preclinical assays[J].Clin Cancer Res,2007,13(13):3989-3998.

    • [22] WEI B R,HOOVER S B,PEER C J,et al.Efficacy,tolerability and pharmacokinetics of combined targeted MEK and dual mTORC1/2 inhibition in a preclinical model of mucosal melanoma[J].Mol Cancer Ther,2020,19(11):2308-2319.

    • [23] DANIEL V C,MARCHIONNI L,HIERMAN J S,et al.A primary xenograft model of small-cell lung cancer reveals irreversible changes in gene expression imposed by culture in vitro[J].Cancer Res,2009,69(8):3364-3373.

    • [24] KEYSAR S B,ASTLING D P,ANDERSON R T,et al.A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in de-fined molecular bins[J].Mol Oncol,2013,7(4):776-790.

    • [25] MIGLIARDI G,SASSI F,TORTI D,et al.Inhibition of MEK and PI3K/mTOR suppresses tumor growth but does not cause tumor regression in patient-derived xenografts of RAS-mutant colorectal carcinomas[J].Clin Cancer Res,2012,18(9):2515-2525.

    • [26] VON HOFF D D,ERVIN T,ARENA F P,et al.Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine[J].N Engl J Med,2013,369(18):1691-1703.

    • [27] BERTOTTI A,MIGLIARDI G,GALIMI F,et al.A molecularly annotated platform of patient-derived xenografts("xenopatients")identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer[J].Cancer Discovery,2011,1(6):508-523.

    • [28] JULIEN S,MERINO-TRIGO A,LACROIX L,et al.Characterization of a large panel of patient-derived tumor xenografts representing the clinical heterogeneity of human colorectal cancer[J].Clin Cancer Res,2012,18(19):5314-5328.

    • [29] SEBASTIANI V,RICCI F,RUBIO-VIQUEIRA B,et al.Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer:relationship to molecular mechanisms of gemcitabine resistance and survival[J].Clin Cancer Res,2006,12(8):2492-2497.

    • [30] RUBIO-VIQUEIRA B,JIMENO A,CUSATIS G,et al.An in vivo platform for translational drug development in pancreatic cancer[J].Clin Cancer Res,2006,12(15):4652-4661.

    • [31] KEYSAR S B,ASTLING D P,ANDERSON R T,et al.A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in defined molecular bins[J].Mol Oncol,2013,7(4):776-790.

    • [32] DAS T M,SALANGSANG F,LANDMAN A S,et al.Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance[J].Nature,2013,494(7436):251-255.

    • [33] CHEN Z,CHENG K,WALTON Z,et al.A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response[J].Nature,2012,483(7391):613-617.

    • [34] DING N,CUI X X,GAO Z,et al.A triple combination of atorvastatin,celecoxib and tipifarnib strongly inhibits pancreatic cancer cells and xenograft pancreatic tumors[J].Int J Oncol,2014,44(6):2139-2145.

    • [35] GARRIDO-LAGUNA I,TAN A C,USON M,et al.Integrated preclinical and clinical development of mTOR inhibitors in pancreatic cancer[J].Br J Cancer,2010,103(5):649-655.

    • [36] DONG X,GUAN J,ENGLISH J C,et al.Patient-derived first generation xenografts of non-small cell lung cancers:promising tools for predicting drug responses for personalized chemotherapy[J].Clin Cancer Res,2010,16(5):1442-1451.

    • [37] MURAYAMA T,GOTOH N.Patient-derived xenograft models of breast cancer and their application[J].Cells,2019,8(6):621.

    • [38] JUNTTILA M R,DE SAUVAGE F J.Influence of tumor micro-environment heterogeneity on therapeutic response[J].Nature,2013,501(7467):346-354.

    • [39] KALSCHEUER H,DANZL N,ONOE T,et al.A model for personalized in vivo analysis of human immune responsiveness[J].Sci Transl Med,2012,4(125):125r-130r.

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