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终点的问题 源自患者的类器官模型 (μPTM) 是组织工程 3D 肿瘤。 可以在微流体装置内生长，形成多细胞组织样结构，保留 这些 μPTM 提供了一个强大的模型。 个体患者的肿瘤，用于药物发现、癌症研究和个性化医疗。 然而，与异种移植肿瘤不同，μPTM 与正电子不相容，这仍然是一个关键障碍。 肿瘤学中使用的发射断层扫描（PET）和其他诊断成像工具非常缺乏。 定量成像方法可以无缝应用于体外细胞等物理尺度 通过广泛的前期工作，我们将在这一点上架起桥梁。 利用放射发光显微镜 (RLM) 对临床放射性核素进行成像的能力 完成后，该项目将实现体外常规成像。 使用越来越多的诊断和治疗放射性药物的肿瘤模型，其中许多是 作为临床护理标准，这一目标将通过追求三个具体目标来实现。 证明可以使用 PET 示踪剂在源自患者的数据中获取基于图像的定量指标 将对来自小鼠异种移植模型的三种 PET 示踪剂进行验证。 其次，我们将通过纳入功能性（可灌注）人类来完善 μPTM。 3D 矩阵内的微血管网络，并使用成像和其他测定法确定 第三，作为一项试点转化研究，我们将开发针对特定患者的研究。 μPTM (n=10) 并比较这些类器官中的氟脱氧葡萄糖 (FDG) 代谢活性 总而言之，该项目将增强研究人员的运行能力。 使用患者自身的肿瘤和临床批准的放射性药物进行“芯片上”临床试验。 最终，这些进步可以转化为预测新药的功效、测试生物学假设、 并对患者进行个体化治疗。