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: 10203876
• 负责人: Jenny J. Yang
• 金额: $ 38.16万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203876
• 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; detection limit; 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.

抽象的 分子成像对于表征肿瘤，肿瘤微环境（MTE）和的动态变化至关重要 多尺度上的肿瘤 - 基质相互作用。转移性肝癌，起源于不同的主要部位 （即，乳腺癌，结肠和紫veal黑色素瘤（UM））具有共同的病理结节和浸润模式，但 对不同类型的治疗反应的多种关键生物标志物的差异表达。成像这些 差异性生长模式非侵入性是一种重要的未满足的医疗需求。但是，精度 通过缺乏安全有效的MRI对比剂和方法，通过MRI进行的分子成像受到了阻碍。 该项目的目的是提高和验证精密分子MR成像的多色能力 （PMRIM）用于简单地量化天然肿瘤环境中的多个分子生物标志物 允许早期检测转移酶，并提供针对一组肝分子的指导疗法 签名。我们对人肝转移的初步组织学分析提供了第一个证据 CXCR4，VEGFR和胶原蛋白I暴露了转移性，血管生成和微观的变化 UM肝转移小鼠模型的癌症开始和进展过程中的环境。目标1是发展 “多色”蛋白分子对比剂（procasm），用于简单地定量多种生物标志物。 我们将使用各种方法来确定金属结合亲和力和选择性以及靶向结合能力。 我们将在不同的田间强度下发展和验证放松特性和多对比性能力 使用多对比度磁共振指纹方法（MC-MRF）。目标2是发展和 验证多种细胞系和外植物肝脏中的多色分子MR成像方法（PMRIM）。这 将确定PMRIM的多个生物标记物细胞表达的敏感性和特异性 并与荧光和组织学分析相比。