Tryptophan metabolism in human brain tumors

人脑肿瘤中的色氨酸代谢

基本信息

批准号：
8627863
负责人：
CSABA JUHASZ
金额：
$ 34.05万
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 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8627863
关键词：
Address Aftercare Amino Acids Applications Grants Aryl Hydrocarbon Receptor Astrocytoma Biological Assay Blood Volume Brain Brain Neoplasms Cell Cycle Cell Density Cells Characteristics Clinical Clinical Trials Data Detection Development Diagnosis Early Diagnosis Edema Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Excision Genetic Transcription Glioma Goals Grant Histopathology Human Image Immunologic Markers Immunosuppression Immunosuppressive Agents Infiltration Interleukin-10 Kinetics Kynurenine Lead Ligands Location Magnetic Resonance Imaging Malignant - descriptor Malignant Glioma Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Metabolic Metabolism Metastatic malignant neoplasm to brain Monitor Newly Diagnosed Operative Surgical Procedures Outcome Pathway interactions Patients Perfusion Play Positron-Emission Tomography Primary Brain Neoplasms Process Proteins Radiation Injuries Recurrence Research Role Sampling Solid Neoplasm Specimen Surrogate Markers Techniques Testing Therapeutic Time Tissue Sample Tracer Tryptophan Tryptophan 2,3 Dioxygenase Tryptophan Metabolism Pathway Tryptophanase Tumor Tissue Vascularization brain tissue chemoradiation density enzyme activity improved indexing inhibitor/antagonist malignant breast neoplasm malignant phenotype molecular imaging neoplastic cell neuroimaging novel novel therapeutics outcome forecast public health relevance radiotracer receptor receptor expression therapy design treatment response tumor tumor progression uptake

项目摘要

DESCRIPTION (provided by applicant): Despite improved diagnosis and therapeutic options, prognosis of patients with brain tumors remains poor. The overall goal of our research, as outlined in this renewal grant application, is to improve diagnosis and treatment of human brain tumors by exploiting mechanisms related to tumoral abnormalities of tryptophan metabolism. In the first grant period, we used molecular imaging with the PET radiotracer ¿[11C]-methyl-L-tryptophan (AMT) to detect and differentiate newly diagnosed and recurrent gliomas. AMT is different from several other amino acid PET tracers in that rather than being incorporated into proteins it is metabolized via the immunosuppressive kynurenine pathway, which is upregulated in various cancers. Using AMT tracer kinetic analysis we were able to estimate tumor proliferative activity, differentiate low-grade glioma types, and distinguish recurrent gliomas fro radiation injury. On co-registered, fused PET/MRI images, we have also observed AMT accumulation beyond the MRI-detected tumor mass, in tumor-infiltrated brain tissue. This is in keeping with the notion that glioma cells infiltrate variably beyond the solid tumor mass into the surrounding brain parenchyma. Building upon our preliminary data, in Aim 1 of the proposed studies we will use the degree of AMT accumulation, measured non-invasively on PET, as a surrogate marker of tumor cell density in tumor-infiltrated brain parenchyma. We will validate this by detailed histopathologic comparisons and then determine whether the extent of PET-defined tumor removal is a predictor of post-surgical tumor recurrence; we will also differentiate primary gliomas from common brain metastases by AMT uptake characteristics. In Aim 2, we will assess the accuracy of quantitative AMT PET and perfusion MRI in patients treated for malignant astrocytic gliomas by post-surgery chemoradiation for differentiating early tumor progression (d6 months after initial treatment) from pseudo-progression, a recently emerged clinical dilemma. We will also test the value of these neuroimaging techniques in predicting the time and location of late (>6 months) tumor recurrence as well as survival before signs of progression on conventional MRI. In Aim 3 we will study mechanisms of tryptophan metabolism in tumor samples obtained from gliomas and common metastatic brain tumors. We will focus on histopathologic and imaging correlates of tumoral kynurenine, the central metabolite of the kynurenine pathway. Kynurenine can be produced by two key enzymes (indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase) and is a recently recognized endogenous ligand for the aryl hyrocarbon receptor (AHR), an important cell-cycle regulator whose activation plays a role in both tumor progression and immune suppression. The expected results will lead to novel treatment approaches targeting tumoral tryptophan-to-kynurenine metabolism (that could be blocked by specific enzyme inhibitors) and/or modulating AHR-mediated transcription. We will also assess AMT metabolic rates, estimated by PET, as an imaging marker of tumoral immune suppression. This will be useful to monitor treatment response in clinical trials of emerging inhibitors.

描述（通过应用提供）：尽管诊断和治疗选择得到改善，但脑肿瘤患者的预后仍然很差。如本续集授予赠款所概述的那样，我们研究的总体目标是通过利用与色氨酸代谢的肿瘤异常相关的机制来改善人脑肿瘤的诊断和治疗。在第一个赠款期间，我们将分子成像与PET radiotracer�[11C] -Methyl-L- tryptaphan（AMT）一起检测并区分了新诊断和反复的神经胶质瘤。 AMT与其他几个氨基酸宠物示踪剂不同，因为它不是被掺入蛋白质中，而是通过免疫抑制性kynurenarine途径代谢，该途径在各种癌症中进行了更新。使用AMT示踪剂动力学分析，我们能够估计肿瘤增殖活性，区分低度胶质瘤类型，并区分复发性神经胶质瘤和辐射损伤。在共同注册，融合的PET/MRI图像上，我们还观察到在肿瘤浸润的脑组织中，AMT的积累超出了MRI检测到的肿瘤质量。这与胶质瘤细胞浸润到周围的脑实质中的渗透率可变多样化的观念一致。在我们的初步数据的基础上，在拟议的研究的目标1中，我们将使用AMT积累的程度，该程度以PET无创测量，作为肿瘤侵蚀性脑实质中肿瘤细胞密度的替代标志物。我们将通过详细的组织病理学比较来验证这一点，然后确定宠物定义的肿瘤清除程度是否是手术后肿瘤复发的预测指标。我们还将通过AMT摄取特征将原发性神经胶质瘤与常见的脑转移区分开。在AIM 2中，我们将通过手术后化学放疗治疗的恶性星形胶质细胞神经胶质瘤的患者评估定量AMT PET和灌注MRI的准确性，以通过伪造的早期肿瘤进展（初次治疗后D6个月）与最近出现的临床困境区分。我们还将测试这些神经影像学技术在预测（> 6个月）肿瘤复发的时间和位置以及在常规MRI进展迹象之前的生存中的价值。在AIM 3中，我们将研究从神经胶质瘤和常见转移性脑肿瘤获得的肿瘤样品中色氨酸代谢的机制。我们将重点关注肿瘤蛇尿氨酸的组织病理学和成像相关，这是Kynurenine途径的中央代谢产物。可通过两种关键酶（吲哚胺2,3-二加氧酶和色氨酸2,3-二氧酶）生产，是一种最近公认的芳基羟基碳受体（AHR）的内源性配体，这是一种重要的细胞周期调节剂，其激活在TumoSnospoppression和Tumosunosunoseplession中起着作用。预期的结果将导致针对肿瘤色氨酸至京脲代谢的新型治疗方法（可以通过特定的酶抑制剂阻断）和/或调节AHR介导的转录。我们还将评估由PET估计的AMT代谢率，作为肿瘤免疫抑制的成像标记。这对于在新兴抑制剂的临床试验中监测治疗反应非常有用。