Sensitivity enhanced MRI imaging of receptor binding in breast cancer

乳腺癌受体结合的灵敏度增强 MRI 成像

基本信息

批准号：
9899981
负责人：
Nirbhay Narayan Yadav
金额：
$ 20.2万
依托单位：
HUGO W. MOSER RES INST KENNEDY KRIEGER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899981
关键词：
Acids Affinity Anatomy Animals Asses Bathing Binding Breast Breast Cancer Cell Caffeine Cancer Patient Cause of Death Cell Line Cell surface Cells Chemicals Clinic Clinical Contrast Media Coupling Detection Development Diagnosis Discipline of Nuclear Medicine Drug Targeting Early Diagnosis Ensure Equipment Exhibits FDA approved Frequencies Funding Glucose Glutamates Glycogen Glycolysis Goals Human Image Imaging Techniques Immobilization In Vitro Industrialization Infusion procedures Isotopes Label Ligand Binding Ligands Magnetic Resonance Imaging Magnetism Malignant Neoplasms Mediating Metabolism Methods Modality Modification Molecular Molecular Probes Molecular Target Monitor Nature Neoplasm Metastasis Outcome Peptides Pharmaceutical Preparations Physiologic pulse Positron-Emission Tomography Proteins Protocols documentation Protons Relapse Resolution Scheme Serum Proteins Signal Transduction Solid Specificity Techniques Technology Translating Water base cancer subtypes cancer type cell type crosslink design experimental study glucosaminoglycans imaging approach imaging modality in vivo individual patient interest link protein malignant breast neoplasm molecular imaging molecular pump myoinositol non-invasive monitor novel outcome forecast personalized medicine pre-clinical radio frequency receptor receptor binding soft tissue solute targeted imaging targeted treatment theranostics therapeutic target tool treatment planning treatment response tumor tumor heterogeneity tumorigenesis

项目摘要

Cancer remains one of the leading causes of death in the industrialized world. In recent years, there has been a resurgence of interest in tumor lactate metabolism since lactate has been associated with metastases and poor prognosis in cancer patients. Recent discoveries have identified that the cell surface lactate receptor HCA1 is associated with tumorigenesis and metastasis and thus an attractive imaging target and possible therapeutic target. However, because lactate exhibits low affinity and a fast turnover rate, current in vivo molecular imaging techniques are not well suited to image these types of targets. We have developed a novel MRI based approach for detecting the low affinity binding of natural (no chemical modification) substrates to molecular targets and a unique molecular pump scheme that enhances the sensitivity two to three orders of magnitude thus making this technology applicable for in vivo studies. Importantly, this method can be implemented on standard MRI hardware and thus rapidly translated to the clinic. We propose developing, optimizing, and validating this approach for imaging the binding of lactate to HCA1 receptors in breast cancer. In AIM 1, we will validate the specificity of detecting lactate-HCA1 binding in vitro using (i) perfused breast cancer cells that express different levels of the HCA1 receptor, and (ii) MRI pulse sequence optimization. In AIM 2, we will validate the specific binding of lactate to breast cancer cells in vivo. We will further probe lactate binding using the infusion of L-lactate or D-glucose (metabolized to lactate), both FDA approved for iv use in humans. These aims are expected to result in a MRI method for imaging the binding of low-affinity ligands to a cell target. Due to the nature of the labelling approaches, these MRI methods will be highly tunable to a broad range of other substrates-target pairs.

癌症仍然是工业化世界的主要原因之一。近年来，出现了由于乳酸与转移有关，因此人们对肿瘤乳酸代谢的兴趣重新燃起癌症患者预后不良。最近的发现发现细胞表面的乳酸受体 HCA1 与肿瘤发生和转移相关，因此是一个有吸引力的成像靶点，并且可能治疗目标。然而，由于乳酸亲和力低且周转率快，目前在体内分子成像技术不太适合对这些类型的目标进行成像。我们开发了一本小说基于 MRI 的方法，用于检测天然（无化学修饰）底物与分子靶点和独特的分子泵方案，可将灵敏度提高两到三个数量级幅度，从而使该技术适用于体内研究。重要的是，这个方法可以在标准 MRI 硬件上实施，从而迅速转化为临床。我们建议开发，优化并验证这种方法对乳腺癌中乳酸与 HCA1 受体的结合进行成像。在 AIM 1 中，我们将使用 (i) 灌注来验证体外检测乳酸-HCA1 结合的特异性表达不同水平 HCA1 受体的乳腺癌细胞，以及 (ii) MRI 脉冲序列优化。在 AIM 2 中，我们将在体内验证乳酸与乳腺癌细胞的特异性结合。我们将使用 L-乳酸或 D-葡萄糖（代谢为乳酸）输注进一步探测乳酸结合，两者均为 FDA 批准用于人类静脉注射。这些目标预计将产生一种 MRI 方法，用于对低亲和力配体与一个细胞目标。由于标记方法的性质，这些 MRI 方法将高度可调以适应广泛的其他底物-目标对。