肿瘤类器官研究现状与展望

doi:10.19401/j.cnki.1007-3639.2024.08.006

摘要/Abstract

摘要：

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。

关键词: 类器官, 器官芯片, 恶性肿瘤

Abstract:

Tumor organoids, derived from tumor tissues, are three-dimensional structures created in vitro to mimic in vivo tumor growth. They possess comparable genetic lineage and pathological characteristics to the original tumor, making them a promising research platform for studying tumor biology. In recent years, significant advancements in techniques such as microfluidics, cell co-culture and vascularization have greatly promoted the development of Organ-on-a-Chip (OoC) and expanded the applications of tumor organoid models in both basic and clinical translational research. These advancements include leveraging tumor organoid models to investigate drug resistance mechanisms, perform drug screening, and facilitate clinical trials of precisional therapy. However, current organoid models still face several limitations, including the instability of cell culture quality, low cost-effectiveness, and the inability to accurately replicate the complex tumor microenvironment and spatial structures. Further research is needed to overcome these technical bottlenecks and improve the application of organoid models in cancer research, thereby further enhancing the depth of tumor research. This review summarized the development history and latest progress of tumor organoids. In terms of the latest applications of tumor organoids, this article reviewed disease modeling, research and development of innovative tumor drugs, and their application in personalized treatment. It also summarized the recent clinical researches of organoids; In addition, this review provided a detailed introduction to the technological progress of tumor organoids, including the development of novel culture devices, simulation of tumor microenvironment, and induction of angiogenesis. In summary, this review explored the latest developments, defects and future directions in the research of tumor organoids, aiming to provide reference for the study of tumor organoids.

Key words: Organoid, Organ-on-a-chip, Malignant tumor

中图分类号:

R73-3

肖毅, 吴名, 姚刚. 肿瘤类器官研究现状与展望[J]. 中国癌症杂志, 2024, 34(8): 763-776.

XIAO Yi, WU Ming, YAO Gang. Research progress and future perspectives of tumor organoid[J]. China Oncology, 2024, 34(8): 763-776.

图/表 4

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类器官指导的干预性临床试验汇总"

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

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