Use of microfluidics for 3D-culturing of patient-derived prostate cancer tissues and preclinical screening of personalized treatment strategies

近年来，前列腺癌（PCa）的基因组和转录组学分析使得能够识别分子改变以及靶向的新途径。然而，新知识的临床意义的同步翻译既没有成功，也没有导致患者结局的显着变化。这是由于目前可用的研究模型不足以对临床高度可变的PCa进行概念验证测试。为了解决这些限制，已经开发了基于微流体系统的“芯片上搭接（lap-on-chip）”概念。患者来源的微解剖肿瘤（MDT）组织通过在由若干通道组成的微流体装置中进行3D培养而产生，所述通道反映患者的肿瘤内异质性。具有平行流体通道的装置可以捕获多个MDT，这些MDT可以用不同的治疗剂孵育和治疗。目前，在一个装置中可以同时将多达32个MDT暴露于各种治疗剂，同时通过特定测定来评估组织的治疗反应。MDT被证明是研究异质性相关现象（如对治疗的抵抗或免疫反应）的一种非常强大的方法。由于这种临床前“芯片上”技术代表了一种类似体内的模型，因此它是大型动物实验的潜在替代品，以证明治疗策略。该项目旨在利用微流控装置进行个性化医疗意义上的患者相关PCa研究和高通量治疗筛选。微流体平台将有助于对从根治性前列腺切除术或前列腺活检获得的患者组织进行直接药物测试。 通过改进新型治疗临床试验的患者分层，预期患者获益最大。该项目的主要目标包括：i）在微流控装置中建立来自不同来源的PCa细胞的3D培养; ii）利用MDT芯片技术测试不同的治疗策略;和iii）分析肿瘤的分子生物学特征以及揭示与治疗反应的相关性。总之，我们的目标是，为需要进一步（辅助）治疗的高危或晚期前列腺癌患者建立预测测试（“个性化药物筛选”），以及鉴定治疗反应的可能的预测生物标志物。在这方面，手术不仅可以作为一种初步的治疗方法，而且可以作为一种有效的获取适当的材料从供体肿瘤。患者的组织又可用于在初始辅助治疗之前确定生物学行为和药物敏感性。此外，微流控平台有助于将新发现从基础研究快速有效地转移到临床评估中。

In recent years, the genomic and transcriptomic analysis of prostate cancer (PCa) enabled the identification of both, molecular alterations as well as novel pathways to target. However, the simultaneous translation of the new knowledge toward clinical implication has neither been successful nor led to significant changes of patient outcomes. This is due to the fact that currently available research models are insufficient for proof-of-concept testing of clinically highly variable PCa. To address these limitations, the "lap-on-chip" concept based on microfluidic systems has been developed. Patient-derived micro-dissected tumor (MDT) tissue is generated by 3D-culturing in a microfluidic device composed of several channels, which mirror the patient’s intra-tumor heterogeneity. Devices with parallel fluidic channels can trap multiple MDTs which can be incubated and treated with different therapeutics. Currently up to 32 MDTs can simultaneously be exposed to various therapeutic agents in one device, while the therapeutic response of the tissue is evaluated by specific assays. MDTs turned out to be an extremely powerful approach to study heterogeneity-related phenomena such as resistance or immune-based responses to treatment. Since this preclinical „on-chip" technology represents an in vivo-like model, it is a potential substitute for large animal experiments to prove therapeutic strategies. This project aims to utilize microfluidic devices for patient-relevant PCa research and high-throughput therapy screening within the meaning of personalized medicine. The microfluidic platform will facilitate direct drug testing on patient tissues obtained from radical prostatectomy or prostate biopsy. By refining patient stratification for clinical trials of novel treatments a maximum benefit for patients is expected. The main goals of this project include i) establishing the 3D-culturing of PCa cells from different origins in microfluidic devices; ii) utilizing the MDT chip technology to test different therapeutic strategies; and iii) analyzing molecular biological signatures of the tumors as well as revealing correlations with therapeutic responses.In summary we aim both, to establish a predicting test (“personalized drug screening”) for patients with high-risk or advanced prostate cancer undergoing surgery who need further (adjuvant) therapy as well as to identify possible predictive biomarkers for therapy response. In this regard, surgery could not only serve as an initial therapeutic approach but also as an effective acquisition of appropriate material from a donor tumor. The patient’s tissue can in turn be used to determine the biological behavior and drug-sensitivity prior to an initial adjuvant treatment. Furthermore, a microfluidic platform facilitates a quick as well as effective transfer of new findings from basic research into clinical evaluation.