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）的基因组学和转录组学分析使得分子改变和新的靶向途径都得到了识别。然而，将新知识同步转化为临床意义既没有成功，也没有导致患者预后的显著变化。这是因为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，基于微流体系统的“片上处理”概念已经被开发出来。患者来源的微解剖肿瘤（MDT）组织是在由多个通道组成的微流控装置中通过3d培养产生的，这反映了患者肿瘤内的异质性。具有平行流体通道的装置可以捕获多个mdt，这些mdt可以用不同的治疗方法孵育和处理。目前，多达32个MDTs可以同时在一个设备中暴露于各种治疗剂，而组织的治疗反应是通过特定的测定来评估的。mdt被证明是一种非常有效的方法来研究异质性相关现象，如对治疗的耐药性或基于免疫的反应。由于这种临床前“芯片”技术代表了一种体内模型，因此它是证明治疗策略的大型动物实验的潜在替代品。本项目旨在利用微流控装置进行个体化医疗意义下的患者相关PCa研究和高通量治疗筛选。微流控平台将有助于对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。通过改进患者分层的新治疗的临床试验，最大限度地造福于患者的期望。该项目的主要目标包括i)在微流体装置中建立不同来源的PCa细胞的3d培养；ii)利用MDT芯片技术测试不同的治疗策略；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手术患者建立一种预测试验（“个性化药物筛选”），并确定治疗反应的可能预测性生物标志物。在这方面，手术不仅可以作为最初的治疗方法，而且可以有效地从供体肿瘤中获取适当的材料。患者的组织可以反过来用于确定生物学行为和药物敏感性之前的初始辅助治疗。此外，微流控平台有助于将基础研究的新发现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.