Preclinical microphysiological tumor models for nuclear medicine

摘要 该项目解决了目前缺乏可量化的和临床相关的成像端点的问题 病人衍生的器官模型。微生理肿瘤模型(μPTM)是一种组织工程化的三维肿瘤 可以在微流控设备内生长，形成多细胞组织样结构，保持 起源组织的生物学和功能特征。这些μPTM提供了强大的 用于个体患者的肿瘤，并用于药物发现、癌症研究和个性化医学。 然而，一个关键的障碍仍然是，与异种移植肿瘤不同，μPTM与正电子不相容。 放射断层扫描(PET)和其他用于肿瘤学的诊断成像工具。这是一个稀缺的 可以在物理范围内无缝应用的定量成像方法，从体外细胞 培养动物模型和癌症患者。从广泛的前期工作中，我们将弥合这一点 GAP通过利用放射发光显微镜(RLM)成像临床放射性核素的能力 具有超高空间分辨率的有机化合物。该项目完成后，将能够进行常规的体外成像 使用越来越多的诊断和治疗性放射性药物的肿瘤模型，其中许多是 用作临床护理标准。这一目标将通过追求三个具体目标来实现。首先，我们将 演示基于图像的量化指标可以使用PET示踪剂在患者来源的 有机化合物。将对三种PET示踪剂与来自 同一组癌症患者。其次，我们将通过结合功能性(可灌流的)人类来改进μPTM 3D基质内的微血管网络，并使用成像和其他分析方法确定 基于图像的终端上的血管系统。第三，作为一项试验性的翻译研究，我们将开发针对患者的 μPTMS(n=10)，并将这些有机物中的氟代脱氧葡萄糖代谢活性与 来自临床FDG-PET的生物标志物。总之，该项目将增强研究人员的运行能力 临床试验“在芯片上”，使用患者自己的肿瘤和临床批准的放射性药物。 最终，这些进展可能被转化为预测新药的疗效，检验生物学假说， 并对患者进行个体化治疗。

Abstract This project addresses the current lack of quantifiable and clinically relevant imaging endpoints for use in patient-derived organoid models. Microphysiological tumor models (μPTMs) are tissue-engineered 3D tumors that can be grown inside microfluidic devices to form multicellular tissue-like constructs that retain the biological and functional characteristics of the tissue of origin. These μPTMs provide a powerful model of individual patients’ tumor and are used in drug discovery, cancer research, and personalized medicine. However, a critical hurdle remains that, unlike xenotransplanted tumors, μPTMs are incompatible with positron emission tomography (PET) and other diagnostic imaging tools used in oncology. There is a dearth of quantitative imaging methods that can be applied seamlessly across physical scales, ranging from in vitro cell cultures to animal models and cancer patients. Drawing from extensive preliminary work, we will bridge this gap by harnessing the ability of radioluminescence microscopy (RLM) to image clinical radionuclides in organoids with ultra-high spatial resolution. Upon completion, this project will enable routine imaging of in vitro tumor models using the growing array of diagnostic and therapeutic radiopharmaceuticals, many of which are used as clinical standard of care. This goal will be achieved by pursuing three specific aims. First, we will demonstrate that quantitative image-based metrics can be acquired using PET tracers in patient-derived organoids. Validation will be conducted for three PET tracers against mouse xenograft models derived from the same set of cancer patients. Second, we will refine the μPTMs by incorporating functional (perfusable) human microvascular networks within the 3D matrix and, using imaging and other assays, determine the effect of the vasculature on image-based endpoints. Third, as a pilot translational study, we will develop patient-specific μPTMs (n=10) and compare fluorodeoxyglucose (FDG) metabolic activity in these organoids against biomarkers derived from clinical FDG-PET. In sum, this project will enhance the ability of researchers to run clinical trials “on a chip”, using the patient’s own tumor and clinically approved radiopharmaceuticals. Ultimately, these advances could be translated to predict the efficacy of new drugs, test biological hypotheses, and individualize patient therapy.