Tryptophan Metabolism in Human Brain Tumors

人脑肿瘤中的色氨酸代谢

• 批准号: 7536039
• 负责人: CSABA JUHASZ
• 金额: $ 30.11万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-03 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7536039
• 关键词: ATP-Binding Cassette Transporters; Address; Adenine; Adult; Amino Acids; Behavior; Biological; Biological Assay; Blood; Brain; Brain Neoplasms; Cause of Death; Cell Proliferation; Cerebrum; Child; Clinical; Complex; Data; Detection; Development; Diagnosis; Dinucleoside Phosphates; Drug resistance; Enzymes; Essential Amino Acids; Excision; Glioblastoma; Glioma; Hamartoma; Human; Image; Immunosuppression; In Vitro; Kinetics; Kynurenine; Label; Lead; Lesion; Malignant Neoplasms; Measurement; Measures; Mediating; Membrane Transport Proteins; Metabolic; Metabolism; Molecular; Multi-Drug Resistance; Necrosis; P-Glycoproteins; Pathway interactions; Patients; Pharmacological Treatment; Pharmacotherapy; Positron-Emission Tomography; Protein Biosynthesis; Radiation; Radiation therapy; Recurrence; Recurrent tumor; Resected; Residual state; Resistance; Role; Serotonin; Solid Neoplasm; Staging; T-Lymphocyte; Testing; Therapeutic; Tissues; Tracer; Tryptophan; Tryptophan 2,3 Dioxygenase; Tryptophan Metabolism Pathway; Tumor Cell Line; Tumor Tissue; base; cell growth; clinically relevant; 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; protein expression; radiotracer; tool; tumor; uptake

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）：每年约有13,000人脑肿瘤是死亡原因，这些肿瘤是儿童最常见的固体肿瘤类型。最近的研究表明，可诱导的色氨酸氧化是调节肿瘤细胞增殖和免疫耐药性的重要机制，主要是通过免疫调节酶吲哚胺2,3-二氧酶（IDO）（IDO），kynurenine Pathway的速率限制步骤。我们的初步研究使用正电子发射断层扫描（PET）与示踪剂1- [11C]甲基-L-色氨酸（AMT）显示，在各种脑肿瘤中，AMT的摄取和代谢的增加以及在切除的肿瘤组织中的IDO表达的增加。这些数据表明，这些肿瘤中AMT的积累与色氨酸的代谢增加有关。该应用将解决色氨酸在儿童和成人中脑肿瘤中作用的基本和临床方面。我们将进行定量的PET研究，以测量各种脑肿瘤中AMT的体内摄取和代谢，并将这些发现与肿瘤增殖指数，IDO免疫反应性和多药耐药性（MDR）蛋白相关联。提出了三个目的：（i）确定AMT PET可以在术前与非肿瘤病变区分开，并在初次治疗后检测残留或复发性肿瘤，并区分复发性肿瘤和辐射坏死。 （ii）基于AMT的转运和代谢诱捕度量来区分各种类型的脑肿瘤。 （iii）确定来自PET成像的AMT的动力学参数与肿瘤增殖指数，IDO和多药耐药蛋白表达源自肿瘤组织的组织学测定法。这些研究将使用创新的体内分子成像与AMT PET和体外肿瘤组织研究的创新方法来阐明色氨酸异常摄取和代谢的机制及其在脑肿瘤的生物学行为中的作用。从临床角度来看，我们的研究将建立对原发性和残留/复发性脑肿瘤的AMT PET成像的使用，这继续对准确诊断构成重大挑战。这些发现将为脑肿瘤中异常色氨酸摄取和代谢的机制提供新的见解，并通过靶向色氨酸代谢和MDR蛋白来使用药理学治疗脑肿瘤的药理治疗来开发新策略。该项目将脑肿瘤的PET成像与示踪剂1- [11C]甲基-L- tryptophan以及对免疫调节酶吲哚胺的表达的体外分析2,3-二氧酶（IDO）以及各种多耐药性（MDR）蛋白（MDR）蛋白质在溶解的脑肿瘤组织中。这些发现将改善对原发性和复发性脑肿瘤的诊断，还将为脑肿瘤中色氨酸代谢异常的代谢机制提供新的见解，具有通过靶向色氨酸代谢代谢和MDR蛋白质对脑肿瘤进行药理治疗的新策略的潜力。