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肿瘤类器官研究现状与展望
肖毅, 吴名, 姚刚
中国癌症杂志    2024, 34 (8): 763-776.   DOI: 10.19401/j.cnki.1007-3639.2024.08.006
摘要   (122 HTML7 PDF(pc) (1361KB)(333)  

肿瘤类器官是指来源于患者肿瘤组织的三维结构模型,拥有与亲代肿瘤类似的基因谱系和病理学特征,能够较为准确地模拟肿瘤在体内的微观形态和生长情况,是肿瘤研究的新型体外模型,在研究肿瘤分子生物学特征、高通量筛选药物、指导个体化治疗等方面具有巨大潜力。近年来,细胞共培养、血管化和微流控等技术与类器官模型的融合发展,催生了器官芯片(Organ-on-a-Chip,OoC)等新工具的发展,促进了类器官模型在研究肿瘤耐药机制、筛选敏感药物和指导精准治疗临床试验等肿瘤基础和临床科学研究中的应用。然而,目前类器官模型还存在培养质量不稳定、高通量检测成本高、难以精确模拟肿瘤微环境和空间结构等问题,需要进一步加强研究,克服技术瓶颈,使其更好地应用于肿瘤学研究,进一步提升肿瘤研究水平。本综述对肿瘤类器官的发展历程和最新进展进行总结,在肿瘤类器官的最新应用方面,本文介绍疾病的建模、肿瘤创新药的研发及在个体化治疗方面的应用,并对近期开展的类器官相关临床研究进行汇总;此外,在肿瘤类器官的技术进展方面,本综述详细阐述开发新型培养装置、模拟肿瘤微环境、诱导血管生成等。综上,本综述梳理肿瘤类器官研究的最新进展、不足和未来发展方向,旨在为肿瘤类器官的研究提供参考。


Identifiers Histology Registration year Drug (s) Status Results/goals
- Colorectal cancer[33] Unknown A 87-drug panel Completed This trial enrolled 28 patients and successfully established 19 organoids, out of which 15 were utilized for drug screening. One patient underwent treatment based on the drug sensitivity results of the organoid and showed partial remission after 3 months of evaluation
2014-003811-13 Colorectal cancer[34] 2014 Palbociclib, axitinib, selumetinib, gefitinib Completed This trial enrolled 54 patients and successfully established 31 organoids, of which 25 were utilized for drug screening. Out of the 25 organoids, 19 received drug sensitivity results. Based on these results, 6 patients underwent treatment; however, none of them showed any efficacy
NCT05842187 Pancreatic cancer/gastric cancer 2023 Various clinically approved drugs Recruiting This trial will use organoid models to guide the precision treatment of metastatic pancreatic cancer and gastric cancer
NCT04931394 Pancreatic cancer 2021 Gemcitabine, 5-fluorouracil, paclitaxel, oxaliplatin, irinotecan Recruiting This trial will use organoid models to guide the adjuvant chemotherapy of pancreatic cancer
NCT04931381 Pancreatic cancer 2021 Gemcitabine, 5-fluorouracil, paclitaxel, oxaliplatin, irinotecan Recruiting This trial will use organoid models to guide the chemotherapy of advanced pancreatic cancer
NCT06102824 Breast cancer 2023 Taxane, anthracycline, 5-fluorouracil, gemcitabine, vinorelbine, eribulin, utidelone, carboplatin, sacituzumab govitecan, and trastuzumab deruxtecan Recruiting This trial will use organoid models to guide the treatment of advanced breast cancer
NCT06268652 Breast cancer 2024 Personalized drug library contains 55 drugs approved by the FDA Recruiting This trial will compare the efficacy of organoid-guided personalized treatment with the treatment of physician’s choice in breast cancer
NCT05832398 Colorectal cancer 2023 Oxaliplatin, irinotecan, 5-fluorouracil Recruiting This trial will use organoid models to guide the precise chemotherapy of colorectal cancer
NCT05177432 Breast cancer 2021 10-12 anti-cancer drugs Recruiting This trial will use organoid models to develop a quadratic phenotypic optimization platform (QPOP) to guide the treatment of breast cancer
NCT05669586 Lung cancer 2023 Unknown Recruiting This trial will use organoid models to guide the precise treatment of refractory non-small cell lung cancer
NCT05813509 Ovarian cancer 2022 10 potential clinical therapeutic drugs Recruiting This trial will use organoid models to guide the personalized treatment of ovarian cancer
NCT06246630 Pancreatic neuroendocrine tumor 2024 Various clinically approved drugs Not yet recruiting This trial will use organoid models to guide the treatment of pancreatic neuroendocrine tumors
NCT05024734 Bladder cancer 2022 Epirubicin, mitomycin, gemcitabine, docetaxel Recruiting This trial will use organoid models to guide the treatment of non-muscle invasive bladder cancers
NCT06077591 Solid tumors 2024 Unknown Not yet recruiting This trial will use organoid models and next-generating sequencing to guide the treatment of advanced and inoperable solid tumors
NCT05352165 Colorectal cancer 2023 Oxaliplatin, irinotecan, 5-fluorouracil Not yet recruiting This trial will compare the efficacy of organoid-guided neoadjuvant chemotherapy with traditional neoadjuvant chemotherapy regimens in advanced colorectal cancer
NCT05378048 Abdominal tumors 2022 Unknown Withdrawn This trial will compare the efficacy of organoid-guided personalized treatment with traditional treatment strategies in advanced and inoperable abdominal tumors
NCT04279509 Solid tumors 2019 5-fluorouracil, carboplatin, cyclophosphamide, docetaxel, doxorubicin, gemcitabine, irinotecan, oxaliplatin, paclitaxel, vinorelbine, etoposide, ifosfamide, methotrexate, pemetrexed and topotecan Unknown This trial will use organoid models to conduct high-throughput drug screening to guide the chemotherapy of refractory solid tumors
NCT05267912 Any cancer type 2022 A panel of drugs (chemotherapy, hormonal therapy, targeted therapy) Recruiting This trial is a multi-center study evaluating the feasibility of using organoid models to guide the precision treatment of multiple advanced tumors
NCT04450706 Breast cancer 2021 Unknown Recruiting This trial will use organoid models to guide the precision treatment of metastatic breast cancers
NCT06057298 Colorectal cancer 2021 Oxaliplatin, mitomycin Recruiting This trial will use organoid models to guide the hyperthermic introperitoneal chemotherapy of colorectal cancers with peritoneal metastasis
NCT04842006 Colorectal cancer 2021 Capecitabine, oxaliplatin Recruiting This trial will use organoid models to guide the neoadjuvant and adjuvant therapy of colorectal cancer
NCT05725200 Colorectal cancer 2022 Alectinib, cetuximab, crizotinib, dasatinib, everolimus, encorafenib, gemcitabine, idelalisib, larotrectinib, methotrexate, palbociclib, panobinostat, pembrolizumab, petrozumab, trastuzumab, talazoparib, venetoclax Recruiting This trial will use organoid models to guide the precision treatment of metastatic colorectal cancer
NCT05464082 Breast cancer 2023 Unknown Recruiting This trial will use organoid models to guide the precision treatment of metastatic triple-negative breast cancers
NCT03778814 Lung cancer/solid tumors 2018 Engineering TCR-T cells Recruiting This trial will use organoid models to guide the TCR-T immunotherapy of lung cancers and other solid tumors
NCT05429684 Breast cancer 2021 Trastuzumab, pertuzumab, nab paclitaxel, pyrotinib, capecitabine, T-DM1, everolimus, CDK4/6 inhibitor, aromatase-Inhibitors, anti-PD-1 monoclonal antibody Recruiting This trial will use organoid models to guide the precision treatment of refractory HER2-positive breast cancers
NCT05381038 Solid tumors 2022 Azacitidine, docetaxel, paclitaxel, irinotecan Not yet recruiting This trial will use organoid models to develop a QPOP and CURATE.AI, which will guide the personalized combinatory therapy with azacytidine in solid tumors.
NCT06227065 Bladder cancer 2024 Epirubicin, mitomycin, gemcitabine, docetaxel Not yet recruiting This trial will use organoid models to guide the precise neoadjuvant chemotherapy of low-grade non-muscle invasive bladder cancers
NCT05432518 Glioblastoma 2023 Afatinib, dasatinib, palbociclib, everolimus, olaparib Recruiting This trial will use organoid models to guide the treatment of refractory glioblastoma
NCT05473923 Glioma 2022 Unknown Recruiting This trial will use organoid models to guide the precision treatment of refractory high-grade glioma
NCT05532397 Astrocytoma 2023 Unknown Recruiting This trial will use organoid models to guide the combinatory therapy of refractory high-grade astrocytoma
2020-003395-41 Colorectal cancer 2020 Alectinib, crizotinib, dasatinib, everolimus, gemcitabine, idelalisib, larotrectinib, methotrexate, palbociclib, panobinostat, pembrolizumab, pertuzumab, trastuzumab, talazoparib, venetoclax, cetuximab, encorafinib Recruiting This trial will use organoid models to guide the personalized therapy of colorectal cancers
View table in article
表1 类器官指导的干预性临床试验汇总
正文中引用本图/表的段落
肿瘤创新药物的研发需要经过药物靶点和候选药物选择、临床前安全性和有效性评价、临床试验等一系列过程。传统的临床前研究模型以细胞和动物模型为主,存在速度慢、成本高和效率低等问题,近年来,类器官模型逐渐在药物研发领域崭露头角,表现出良好的应用前景。首先,在评估治疗药物的有效性方面,肿瘤类器官能更好地模拟肿瘤在体内的结构和药物敏感性,为药物测试提供更接近真实的环境,显著缩短药物试验周期、降低成本、提高转化效率。有研究[22-23]报道,利用结直肠癌类器官样本库对超过500种靶向WNT和RTK信号转导通路的双特异性抗体进行高通量的功能筛选,发现MCLA-158(一种LGR5和EGFR双特异性抗体)可以特异性降解Lgr5+肿瘤干细胞表面的EGFR从而杀伤肿瘤,而对正常的结肠类器官毒性很小。次年,MCLA-158仅凭借类器官实验数据就获得了美国食品药品管理局(Food and Drug Administration,FDA)的新药临床试验审批,批准在晚期结直肠癌、胃癌、头颈鳞癌等实体瘤患者中开展Ⅰ/Ⅱ期临床试验(NCT03526835)。2023年,有研究[24]公布了MCLA-158在晚期头颈部鳞癌中的疗效,在接受治疗评估的43位患者中,客观缓解率达37.2%,疾病控制率为72.1%,基于这些临床数据,FDA在同年授予其快速通道的资格认定,这一决定有望加速后续Ⅱ~Ⅲ期临床试验进程和药物上市审批。传统的药物研发流程往往耗时数十年,其中临床前研究平均耗时5年半,需要开展大量细胞和动物实验[25],而MCLA-158从筛选到进入临床试验阶段仅用时1年,使用类器官模型开展临床前研究明显缩短了新药研发时长,降低了研发成本。此外,类器官还可用于药代动力学研究,Onozato等[26]发现,经药物诱导后的肠道类器官中可以检测到药物转运蛋白的表达和药物通过ABCB1/MDR1的外排转运活性,药物代谢酶CYP3A4的表达也会发生诱导性升高,因此,可以利用肠道类器官进行抗肿瘤药物的药代动力学监测。肝脏、肾脏和心脏类器官可用于抗肿瘤药物毒理学研究,了解抗肿瘤药物的肝、肾和心脏毒性。药物相关的肝毒性主要由肝药酶细胞色素P450介导,Katsuda等[27]研究发现肝脏类器官中细胞色素P450的活性与体内情况相当,可以用于监测抗肿瘤药物的肝毒性;Voges等[28]证实,心脏类器官在经历药物毒性损伤后能够发生与体内类似的内源性再生修复,可用于反映药物的心脏毒性;Takasato等[29]的研究结果显示,肾脏类器官在经历药物毒性损伤后会发生形态改变,可以提示药物的肾脏毒性。
目前主要使用基因检测和对特殊蛋白进行免疫组织化学染色等手段指导肿瘤的精准治疗,然而这些方法存在较大的局限性,部分患者无法检测到明确的药物靶点,部分患者即使测到药靶,也可能因为肿瘤生物学特征的复杂性而造成临床实际用药无效,目前模式下真正能够从精准治疗中获益的患者仅占10%左右[31]。基于肿瘤类器官模型开展药敏检测则是结果导向的检测,不受基因突变与基因表达谱改变的影响,可以提供药物敏感性的直接证据,在指导肿瘤的个体化治疗方面具有巨大潜力。截至2024年3月11日,检索两大主要的临床试验登记平台(https://clinicaltrials.gov/和https://www.clinicaltrialsregister.eu)上备案的肿瘤类器官有关的临床研究,结果发现,自2017年以来肿瘤类器官相关的临床研究数量明显增加,近3年呈快速增长趋势(图2A)。从癌种分布上看,结直肠癌相关项目数量最多,达到38项,其次是乳腺癌和胰腺癌,分别为30和23项(图2B)。基于肿瘤类器官的临床研究最主要的模式是前瞻性收集样本开展类器官培养和药敏检测,进而观察类器官的药敏检测结果是否与临床疗效一致。在国内一项名为CinClare的Ⅲ期临床试验中,研究人员在112例局部晚期结直肠癌患者体内获取肿瘤组织构建了96例肿瘤类器官进行培养和药敏检测,发现类器官药敏结果对这些患者新辅助放化疗效果预测的准确率、敏感性和特异性分别达到84.43%、78.01%和91.97%,呈现出很高的临床相关性[32]。2019年以来,基于类器官药敏检测结果开展个体化治疗的干预性临床试验在逐步增多(图2C)。2020年报道的来自澳大利亚的APOLLO临床试验是首个类器官药敏检测指导个体化治疗的临床试验,研究入组了28例多线治疗失败、伴腹膜转移的结直肠癌患者,其中19例利用腹膜转移病灶成功构建了类器官,后续药敏检测验证了这些类器官均对前线治疗中已临床耐药的药物无反应,但发现来源于其中1例患者的类器官对吉西他滨敏感,临床医师依据类器官药敏结果对该患者使用吉西他滨,也确实观察到临床效果即肿瘤发生了退缩[33]。APOLLO临床试验初步证实了基于类器官药敏检测结果开展个体化治疗模式的可行性,为晚期难治性实体瘤患者的治疗提供了潜在的新策略。然而APOLLO临床试验入组患者少、检测时间长(8周)、有效患者寥寥无几,说明这类研究模式仍需要继续探索。2021年来自荷兰的SENSOR临床试验的失败也进一步暴露了这类研究目前存在的问题,该研究入组了54例转移性结直肠癌患者并成功培养了31例肿瘤类器官,其中25例具有足够的细胞量进行1~6种临床可及药物的筛选,19例检测到潜在的治疗敏感药物。然而,由于检测时间长达8~10周,不少患者在治疗前已发生疾病进展而失去治疗机会,最终仅6例患者进行了个体化治疗,且均临床治疗无效[34]。其余在临床试验网站备案的前瞻性临床试验大部分都在进行中,尚无结果报道(表1)。目前类器官指导的干预性临床试验仍处于萌芽阶段,存在样本量较小、类器官药敏检测耗时长、检测结果不稳定和临床试验证据级别不高等问题。尽管如此,我们仍然相信随着类器官技术的发展和临床试验流程的优化,这一新型临床研究模式值得期待。
This review surveyed the https://clinicaltrials.gov and https://www.clinicaltrialsregister.eu in March 11, 2024. The searching key words were “organoid AND cancer”, “organoids AND cancer” or “organ-on-a-chip AND cancer”. Afterwards, we manually checked each clinical trial labeled as "interventional" to confirm whether it was a organoid-based prospective clinical trial. FDA: Food and drug administration; QPOP: Quadratic phenotypic optimization platform; TCR-T: T cell receptor-engineered T cell; CDK: Cyclin-dependent kinases; T-DM1: Trastuzumab emtansine; PD-1: Programmed death 1; HER2: Human epidermal growth factor receptor 2; CURATE.AI: An appropriate dosing strategy over time. ...
Prospective experimental treatment of colorectal cancer patients based on organoid drug responses
2
2021
... 目前主要使用基因检测和对特殊蛋白进行免疫组织化学染色等手段指导肿瘤的精准治疗,然而这些方法存在较大的局限性,部分患者无法检测到明确的药物靶点,部分患者即使测到药靶,也可能因为肿瘤生物学特征的复杂性而造成临床实际用药无效,目前模式下真正能够从精准治疗中获益的患者仅占10%左右[31].基于肿瘤类器官模型开展药敏检测则是结果导向的检测,不受基因突变与基因表达谱改变的影响,可以提供药物敏感性的直接证据,在指导肿瘤的个体化治疗方面具有巨大潜力.截至2024年3月11日,检索两大主要的临床试验登记平台(https://clinicaltrials.gov/和https://www.clinicaltrialsregister.eu)上备案的肿瘤类器官有关的临床研究,结果发现,自2017年以来肿瘤类器官相关的临床研究数量明显增加,近3年呈快速增长趋势(图2A).从癌种分布上看,结直肠癌相关项目数量最多,达到38项,其次是乳腺癌和胰腺癌,分别为30和23项(图2B).基于肿瘤类器官的临床研究最主要的模式是前瞻性收集样本开展类器官培养和药敏检测,进而观察类器官的药敏检测结果是否与临床疗效一致.在国内一项名为CinClare的Ⅲ期临床试验中,研究人员在112例局部晚期结直肠癌患者体内获取肿瘤组织构建了96例肿瘤类器官进行培养和药敏检测,发现类器官药敏结果对这些患者新辅助放化疗效果预测的准确率、敏感性和特异性分别达到84.43%、78.01%和91.97%,呈现出很高的临床相关性[32].2019年以来,基于类器官药敏检测结果开展个体化治疗的干预性临床试验在逐步增多(图2C).2020年报道的来自澳大利亚的APOLLO临床试验是首个类器官药敏检测指导个体化治疗的临床试验,研究入组了28例多线治疗失败、伴腹膜转移的结直肠癌患者,其中19例利用腹膜转移病灶成功构建了类器官,后续药敏检测验证了这些类器官均对前线治疗中已临床耐药的药物无反应,但发现来源于其中1例患者的类器官对吉西他滨敏感,临床医师依据类器官药敏结果对该患者使用吉西他滨,也确实观察到临床效果即肿瘤发生了退缩[33].APOLLO临床试验初步证实了基于类器官药敏检测结果开展个体化治疗模式的可行性,为晚期难治性实体瘤患者的治疗提供了潜在的新策略.然而APOLLO临床试验入组患者少、检测时间长(8周)、有效患者寥寥无几,说明这类研究模式仍需要继续探索.2021年来自荷兰的SENSOR临床试验的失败也进一步暴露了这类研究目前存在的问题,该研究入组了54例转移性结直肠癌患者并成功培养了31例肿瘤类器官,其中25例具有足够的细胞量进行1~6种临床可及药物的筛选,19例检测到潜在的治疗敏感药物.然而,由于检测时间长达8~10周,不少患者在治疗前已发生疾病进展而失去治疗机会,最终仅6例患者进行了个体化治疗,且均临床治疗无效[34].其余在临床试验网站备案的前瞻性临床试验大部分都在进行中,尚无结果报道(表1).目前类器官指导的干预性临床试验仍处于萌芽阶段,存在样本量较小、类器官药敏检测耗时长、检测结果不稳定和临床试验证据级别不高等问题.尽管如此,我们仍然相信随着类器官技术的发展和临床试验流程的优化,这一新型临床研究模式值得期待. ...

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