Multi-color Mapping of Cancer Molecular Signatures and Tumor microenvironment

癌症分子特征和肿瘤微环境的多色绘图

• 批准号: 9980316
• 负责人: Jenny J. Yang
• 金额: $ 38.19万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-18 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980316
• 关键词: Advanced Development; Affinity; Aftercare; Binding; Binding Sites; Biodistribution; Biological Markers; Brain; Breast; CXCR4 gene; Calibration; Cancer Biology; Cell Line; Cells; Collagen; Colon; Color; Combined Modality Therapy; Contrast Media; Coupled; Deposition; Detection; Disease; Drug Kinetics; Early Diagnosis; Environment; Evaluation; Exhibits; Fingerprint; Fluorescence; GD3 Binding; Generations; Goals; Growth; Heterogeneity; Histologic; Human; Image; Immunotherapy; Ions; KDR gene; Kidney; Kinetics; Lesion; Liver; Magnetic Resonance; Magnetic Resonance Imaging; Malignant neoplasm of liver; Maps; Medical; Metals; Metastatic Neoplasm to the Liver; Methodology; Methods; Molecular; Molecular Profiling; Monitor; Mus; Neoplasm Metastasis; Organ; Pathologic; Patients; Pattern; Penetration; Property; Proteins; Quantitative Evaluations; Radiology Specialty; Relaxation; Resolution; Sensitivity and Specificity; Serum; Site; Spatial Distribution; Specificity; Staging; Structure; Techniques; Technology; Three-Dimensional Image; Time; Tissues; Tumor Tissue; Uveal Melanoma; Validation; acute toxicity; angiogenesis; antiangiogenesis therapy; base; biophysical techniques; cancer initiation; cancer type; clinical imaging; contrast enhanced; design; differential expression; drug efficacy; high risk; human tissue; imaging modality; improved; individualized medicine; molecular imaging; molecular marker; mouse model; neoplastic cell; novel; preclinical safety; quantitative imaging; targeted biomarker; treatment response; treatment strategy; tumor; tumor microenvironment; tumor molecular fingerprint; tumor progression; tumor xenograft

Abstract Molecular imaging is critical for characterizing dynamic changes in tumor, tumor microenvironment (MTE), and tumor-stroma interactions at multiscale levels. Metastatic liver cancers that originate from different primary sites (i.e., breast, colon and uveal melanoma (UM)) share common pathological nodular and infiltrative patterns, but differential expressions of multiple key biomarkers that respond to different types of therapy. Imaging these differential pathological growth patterns non-invasively is a significant unmet medical need. However, precision molecular imaging via MRI has been hindered by a lack of safe and effective MRI contrast agents and methods. The goal of this project is to advance and validate the multi-color capability of precision molecular MR Imaging (pMRIm) for simultaneous quantification of multiple molecular biomarkers within the native tumor environment to allow for early detection of metastases and to provide guided therapy tailored to a set of liver molecular signatures. Our preliminary histological analyses of human liver metastases have provided the first evidence that CXCR4, VEGFR, and collagen I exhibit changes of metastatic potential, angiogenesis, and the micro- environment during cancer initiation and progression in UM liver metastasis mouse models. Aim 1 is to develop “multi-color” protein molecular contrast agents (ProCAsm) for simultaneous quantification of multiple biomarkers. We will determine metal binding affinities and selectivities as well target binding capability using various methods. We will develop and validate relaxation properties and multi-contrast capability under different field strengths using multiple-contrast Magnetic Resonance Fingerprinting Methodology (MC-MRF). Aim 2 is to develop and validate multi-color molecular MR imaging methodology (pMRIm) in multiple cell lines and explanted liver. The sensitivity and specificity of quantification of multiple biomarker cellular expression by pMRIm will be determined and compared with fluorescence and histological analysis.

摘要 分子成像对于表征肿瘤、肿瘤微环境（MTE）和肿瘤微环境的动态变化是至关重要的。 多尺度水平的肿瘤-间质相互作用。来源于不同原发部位的转移性肝癌 (i.e.,乳腺、结肠和葡萄膜黑色素瘤（UM））具有共同的病理结节和浸润模式，但 对不同类型的治疗有反应的多种关键生物标志物的差异表达。想象这些 非侵入性的不同病理生长模式是一个显著的未满足的医疗需求。然而，精确 通过MRI的分子成像由于缺乏安全有效的MRI造影剂和方法而受到阻碍。 本项目的目标是推进和验证精密分子磁共振成像的多色能力 （pMRIm）用于同时定量天然肿瘤环境内的多种分子生物标志物， 允许早期检测转移并提供针对一组肝脏分子的指导治疗， 签名.我们对人类肝转移瘤的初步组织学分析提供了第一个证据， CXCR 4、VEGFR和I型胶原蛋白显示出转移潜能、血管生成和微血管生成的变化。 在UM肝转移小鼠模型中研究癌症起始和进展期间的环境。目标1：发展 “多色”蛋白质分子造影剂（ProCAsm）用于同时定量多种生物标志物。 我们将使用各种方法确定金属结合亲和力和选择性以及靶结合能力。 我们将开发和验证不同场强下的弛豫特性和多对比度能力 使用多重对比磁共振指纹法（MC-MRF）。目标二是发展和 在多个细胞系和移植肝脏中验证多色分子MR成像方法（pMRIm）。的 将确定通过pMRI m定量多种生物标志物细胞表达的灵敏度和特异性 并与荧光和组织学分析进行比较。