Preclinical microphysiological tumor models for nuclear medicine

核医学临床前微生理肿瘤模型

• 批准号: 10587674
• 负责人: Guillem Pratx
• 金额: $ 52.99万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587674
• 关键词: 3-Dimensional; Address; Animal Cancer Model; Animal Model; Biocompatible Materials; Biological; Biological Assay; Biological Markers; Biological Process; Biological Testing; Blood Vessels; Cancer Diagnostics; Cancer Model; Cancer Patient; Capillary Permeability; Cell Culture Techniques; Cell Proliferation; Cells; Characteristics; Clinical; Clinical Research; Clinical Trials; Complement; Data; Dedications; Development; Device Designs; Diagnostic; Diagnostic Imaging; Discipline of Nuclear Medicine; Endothelial Cells; Engineering; Environment; Extracellular Matrix; Foundations; Future; Goals; Head and Neck Squamous Cell Carcinoma; Human; Hypoxia; Image; Imaging Device; In Vitro; Laboratories; Measures; Metabolic; Metabolism; Microfabrication; Microfluidic Microchips; Microfluidics; Microscopy; Modeling; Molecular; Mus; Oncology; Optics; Organoids; Patient imaging; Patients; Perfusion; Pharmacologic Substance; Physiological; Physiology; Pilot Projects; Positron; Positron-Emission Tomography; Procedures; Process; Property; Radiation therapy; Radioisotopes; Radionuclide Imaging; Radiopharmaceuticals; Reproducibility; Research; Research Personnel; Resolution; Running; Sampling; Science; Solid Neoplasm; System; Therapeutic; Tissue Engineering; Tissues; Tracer; Translating; Treatment Protocols; Tumor Tissue; Validation; Vascularization; Visualization; With laterality; Work; X-Ray Computed Tomography; Xenograft Model; Xenograft procedure; anticancer research; biomedical imaging; cancer imaging; chemotherapy; clinical imaging; clinical translation; clinical trial on a chip; clinically relevant; cohort; cost; drug discovery; experience; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; head and neck cancer patient; image translation; imaging approach; imaging modality; in vivo; individual patient; instrument; interest; meter; microPET; neovasculature; novel therapeutics; patient response; perfusion imaging; personalized medicine; pre-clinical; pre-clinical research; preclinical study; preclinical trial; predictive test; prospective; quantitative imaging; radiotracer; response; routine imaging; standard of care; stem cells; trafficking; translational study; treatment response; tumor; tumor microenvironment; tumor xenograft; uptake; vascular tissue engineering

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.

抽象的 该项目解决了目前缺乏可量化和临床相关的成像端点以用于 患者衍生的类器官模型。微生物生理肿瘤模型（μPTM）是组织工程的3D肿瘤 可以在微流体设备内生长，以形成多细胞组织样构建体，以保留 起源组织的生物学和功能特征。这些μptms提供了强大的模型 个别患者的肿瘤，用于药物发现，癌症研究和个性化医学。 但是，临界障碍仍然是，与异种移植的肿瘤不同，μptms与阳性不相容 发射断层扫描（PET）和其他用于肿瘤学的诊断成像工具。有死亡 可以在物理尺度上无缝应用的定量成像方法，范围从体外细胞 动物模型和癌症患者的培养物。从广泛的初步工作中汲取灵感，我们将桥梁 通过利用射线发光显微镜（RLM）图像临床放射线的差距 具有超高空间分辨率的器官。完成后，该项目将实现体外的常规成像 使用诊断和治疗性放射性药物阵列不断增长的肿瘤模型，其中许多是 用作临床护理标准。通过追求三个具体目标来实现此目标。首先，我们会的 证明可以使用患者来源的宠物示踪剂来获取基于图像的定量指标 器官。将对三个宠物示踪剂进行验证，以针对源自源自的小鼠异种移植模型 相同的癌症患者。其次，我们将通过合并功能（灌注）人来完善μPTM 3D矩阵中的微血管网络，并使用成像和其他测定法确定 基于图像的端点的脉管系统。第三，作为一项试点翻译研究，我们将开发特定于患者的 μPTM（n = 10），并比较这些器官中的氟脱氧葡萄糖（FDG）代谢活性 源自临床FDG-PET的生物标志物。总而言之，该项目将增强研究人员的运行能力 使用患者自己的肿瘤和临床认可的放射性药物“在芯片上”进行临床试验。 最终，可以翻译这些进步以预测新药的效率，测试生物学假设， 和个性化的患者疗法。