Tryptophan Metabolism in Human Brain Tumors

人脑肿瘤中的色氨酸代谢

基本信息

批准号：
8196842
负责人：
CSABA JUHASZ
金额：
$ 29.19万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-03 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8196842
关键词：
ATP-Binding Cassette Transporters Accounting Address Adenine Adult Aftercare Amino Acids Anaplastic astrocytoma Behavior Biological Biological Assay Blood Brain Brain Neoplasms Cause of Death Cell Proliferation Cells Cerebrum Child Clinical Complex Data Detection Development Diagnosis Dinucleoside Phosphates Drug resistance Ensure Enzymes Essential Amino Acids Excision Glioblastoma Glioma Hamartoma Human Image Immunosuppression In Vitro Inflammatory Kinetics Kynurenine Label Lead Lesion Magnetic Resonance Imaging Malignant Glioma Malignant Neoplasms Measurement Measures Mediating Membrane Transport Proteins Metabolic Metabolism Methods Molecular Multi-Drug Resistance Necrosis Neuropil P-Glycoproteins Pathway interactions Patients Pattern Pharmacological Treatment Pharmacotherapy Positron-Emission Tomography Principal Investigator Process Protein Biosynthesis Radiation Radiation therapy Recurrence Recurrent tumor Resected Residual Tumors Residual state Resistance Role Scheme Serotonin Solid Neoplasm Staging Staining method Stains System T-Lymphocyte Therapeutic Time Tissues Tracer Tryptophan Tryptophan 2,3 Dioxygenase Tryptophan Metabolism Pathway Tumor Cell Line Tumor Tissue Tumor Volume base cell growth design follow-up immunocytochemistry immunoreactivity improved in vivo indexing innovation insight lymphocyte proliferation malformation molecular imaging multi drug transporter neoplastic cell neuronal tumor novel novel therapeutic intervention oxidation performance tests programs protein expression radiotracer response tool tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Brain tumors are the cause of death in approximately 13,000 people in the U.S. every year, and these tumors represent the most common type of solid neoplasms in children. Recent studies have demonstrated that inducible tryptophan oxidation is an important mechanism of modulation of tumor cell proliferation and immuno-resistance, mainly via the immuno-modulatory enzyme indoleamine 2,3-dioxygenase (IDO), the rate-limiting step of the kynurenine pathway. Our preliminary studies using positron emission tomography (PET) with the tracer 1-[11C]methyl-L-tryptophan (AMT) showed differential increase of uptake and metabolism of AMT in various brain tumors, and expression of IDO in resected tumor tissue. These data suggest that accumulation of AMT in these tumors is related to increased metabolism of tryptophan via the kynurenine pathway. This application will address both basic and clinical aspects of the role of tryptophan in brain tumors in children and adults. We will perform quantitative PET studies to measure in vivo uptake and metabolism of AMT in various brain tumors and correlate these findings with tumor proliferative index, IDO immunoreactivity, and multidrug-resistance (MDR) proteins in resected tumor tissues. Three aims are proposed: (i) To establish that AMT PET can differentiate brain tumors from non-tumorous lesions preoperatively, and detect residual or recurrent tumors after initial treatment, as well as differentiate between recurrent tumors and radiation necrosis. (ii) To differentiate among various types of brain tumors based on measures of transport and metabolic trapping of AMT. (iii) To determine the relationship between kinetic parameters of AMT derived from PET imaging, and tumor proliferative index, IDO, and multidrug-resistance protein expression derived from histological assay of tumor tissue. These studies will elucidate mechanisms of abnormal uptake and metabolism of tryptophan and their role in the biological behavior of brain tumors using an innovative approach of combination of in vivo molecular imaging with AMT PET and in vitro tumor tissue studies. From a clinical perspective, our studies will establish the use of AMT PET imaging of primary and residual/recurrent brain tumors, which continue to pose a major challenge for accurate diagnosis. The findings will provide new insight into mechanisms of abnormal tryptophan uptake and metabolism in brain tumors with the potential of developing new strategies using pharmacological treatment of brain tumors by targeting tryptophan metabolism and MDR proteins. This project combines PET imaging of brain tumors with the tracer 1-[11C]methyl-L-tryptophan and in vitro analysis of the expression of the immuno-modulatory enzyme indoleamine 2,3-dioxygenase (IDO) as well as various multidrug-resistance (MDR) proteins in resected brain tumor tissues. The findings will provide improved diagnosis of primary and recurrent brain tumors and also will give new insights into mechanisms of abnormal tryptophan metabolism in brain tumors with the potential of developing new strategies using pharmacological treatment of brain tumors by targeting tryptophan metabolism and MDR proteins.

描述（由申请人提供）：脑肿瘤是美国每年约 13,000 人的死亡原因，这些肿瘤是儿童中最常见的实体肿瘤类型。最近的研究表明，诱导性色氨酸氧化是调节肿瘤细胞增殖和免疫抵抗的重要机制，主要通过免疫调节酶吲哚胺 2,3-双加氧酶 (IDO)（犬尿氨酸途径的限速步骤）实现。我们使用正电子发射断层扫描（PET）和示踪剂1-[11C]甲基-L-色氨酸（AMT）进行的初步研究表明，各种脑肿瘤中AMT的摄取和代谢以及切除的肿瘤组织中IDO的表达存在差异性增加。这些数据表明，这些肿瘤中 AMT 的积累与通过犬尿氨酸途径增加色氨酸代谢有关。该应用将解决色氨酸在儿童和成人脑肿瘤中的作用的基础和临床方面。我们将进行定量 PET 研究，测量各种脑肿瘤中 AMT 的体内摄取和代谢，并将这些发现与肿瘤增殖指数、IDO 免疫反应性和切除肿瘤组织中的多药耐药 (MDR) 蛋白相关联。提出了三个目标：（i）确定 AMT PET 可以在术前区分脑肿瘤和非肿瘤性病变，并在初始治疗后检测残留或复发的肿瘤，以及区分复发性肿瘤和放射性坏死。 (ii) 根据 AMT 转运和代谢捕获的测量来区分各种类型的脑肿瘤。 (iii)确定来自PET成像的AMT动力学参数与来自肿瘤组织的组织学测定的肿瘤增殖指数、IDO和多药耐药蛋白表达之间的关系。这些研究将采用体内分子成像与 AMT PET 和体外肿瘤组织研究相结合的创新方法，阐明色氨酸的异常摄取和代谢机制及其在脑肿瘤生物学行为中的作用。从临床角度来看，我们的研究将建立 AMT PET 成像对原发性和残留/复发性脑肿瘤的使用，这仍然对准确诊断构成重大挑战。这些发现将为脑肿瘤中色氨酸摄取和代谢异常的机制提供新的见解，并有可能开发出通过靶向色氨酸代谢和 MDR 蛋白来药物治疗脑肿瘤的新策略。该项目将脑肿瘤的 PET 成像与示踪剂 1-[11C]甲基-L-色氨酸结合起来，并在体外分析免疫调节酶吲哚胺 2,3-双加氧酶 (IDO) 的表达以及各种多重耐药性（MDR）蛋白在切除的脑肿瘤组织中。这些发现将改善原发性和复发性脑肿瘤的诊断，也将为脑肿瘤中色氨酸代谢异常的机制提供新的见解，并有可能开发出通过靶向色氨酸代谢和MDR蛋白来药物治疗脑肿瘤的新策略。