Ong Louis Jun Ye, Chia Shumei, Wong Stephen Qi Rong, Zhang Xiaoqian, Chua Huiwen, Loo Jia Min, Chua Wei Yong, Chua Clarinda, Tan Emile, Hentze Hannes, Tan Iain Beehuat, DasGupta Ramanuj, Toh Yi-Chin
School of Mechanical, Medical and Process Engineering, Queensland University of Technology (QUT), Brisbane, QL, Australia.
Centre for Biomedical Technologies, Queensland University of Technology (QUT), Brisbane, QL, Australia.
Front Bioeng Biotechnol. 2022 Aug 16;10:952726. doi: 10.3389/fbioe.2022.952726. eCollection 2022.
Inter-patient and intra-tumour heterogeneity (ITH) have prompted the need for a more personalised approach to cancer therapy. Although patient-derived xenograft (PDX) models can generate drug response specific to patients, they are not sustainable in terms of cost and time and have limited scalability. Tumour Organ-on-Chip (OoC) models are alternatives that can recapitulate some aspects of the 3D tumour microenvironment and can be scaled up for drug screening. While many tumour OoC systems have been developed to date, there have been limited validation studies to ascertain whether drug responses obtained from tumour OoCs are comparable to those predicted from patient-derived xenograft (PDX) models. In this study, we established a multiplexed tumour OoC device, that consists of an 8 × 4 array (32-plex) of culture chamber coupled to a concentration gradient generator. The device enabled perfusion culture of primary PDX-derived tumour spheroids to obtain dose-dependent response of 5 distinct standard-of-care (SOC) chemotherapeutic drugs for 3 colorectal cancer (CRC) patients. The efficacies of the chemotherapeutic drugs were rank-ordered for individual patients and compared to the efficacy obtained from matched PDX models. We show that quantitative correlation analysis between the drug efficacies predicted the microfluidic perfusion culture is predictive of response in animal PDX models. This is a first study showing a comparative framework to quantitatively correlate the drug response predictions made by a microfluidic tumour organ-on-chip (OoC) model with that of PDX animal models.
患者间和肿瘤内异质性(ITH)促使人们需要一种更个性化的癌症治疗方法。尽管患者来源的异种移植(PDX)模型可以产生针对患者的药物反应,但它们在成本和时间方面不可持续,并且可扩展性有限。肿瘤芯片器官(OoC)模型是一种替代方案,可以概括3D肿瘤微环境的某些方面,并且可以扩大规模用于药物筛选。尽管迄今为止已经开发了许多肿瘤OoC系统,但确定从肿瘤OoC获得的药物反应是否与从患者来源的异种移植(PDX)模型预测的反应相当的验证研究有限。在本研究中,我们建立了一种多路复用肿瘤OoC装置,该装置由与浓度梯度发生器耦合的8×4阵列(32通道)培养室组成。该装置能够对原发性PDX来源的肿瘤球体进行灌注培养,以获得3例结直肠癌(CRC)患者对5种不同标准护理(SOC)化疗药物的剂量依赖性反应。对每位患者的化疗药物疗效进行排序,并与从匹配的PDX模型获得的疗效进行比较。我们表明,药物疗效之间的定量相关性分析表明,微流控灌注培养可预测动物PDX模型中的反应。这是第一项展示比较框架的研究,用于定量关联微流控肿瘤芯片器官(OoC)模型与PDX动物模型所做的药物反应预测。
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