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（由申请人提供）：尽管诊断和治疗方案有所改善，但脑肿瘤患者的预后仍然很差。正如本次更新拨款申请中概述的那样，我们研究的总体目标是通过利用来改善人类脑肿瘤的诊断和治疗。与肿瘤色氨酸代谢异常相关的机制在第一个资助期间，我们使用 PET 放射性示踪剂进行分子成像。 [11C]-甲基-L-色氨酸 (AMT) 用于检测和区分新诊断和复发的神经胶质瘤，AMT 与其他几种氨基酸 PET 示踪剂不同，因为它不是并入蛋白质中，而是通过免疫抑制犬尿氨酸途径进行代谢。使用 AMT 示踪动力学分析，我们能够估计肿瘤增殖活性、区分低级别神经胶质瘤类型并区分复发性神经胶质瘤。在共同配准的融合 PET/MRI 图像上，我们还观察到 AMT 积累超出了 MRI 检测到的肿瘤肿块，在肿瘤浸润的脑组织中，这与胶质瘤细胞不同程度地浸润到肿瘤肿块之外的观点一致。根据我们的初步数据，在拟议研究的目标 1 中，我们将使用通过 PET 无创测量的 AMT 积累程度作为评估指标。肿瘤浸润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 PET 定义的肿瘤切除程度是否是术后肿瘤复发的预测因子；通过 AMT 摄取特征来评估常见脑转移瘤在目标 2 中，我们将评估定量 AMT PET 和灌注 MRI 对恶性星形胶质细胞治疗患者的准确性。通过术后放化疗区分早期肿瘤进展（初始治疗后 6 个月）和假性进展（这是最近出现的临床困境），我们还将测试这些神经影像技术在预测晚期肿瘤进展（> 6 个月）的时间和位置方面的价值。月）肿瘤复发以及常规 MRI 出现进展迹象之前的生存率。在目标 3 中，我们将研究从神经胶质瘤和常见转移性脑肿瘤中获得的肿瘤样本中的色氨酸代谢机制。肿瘤犬尿氨酸的组织病理学和影像学相关，犬尿氨酸是犬尿氨酸途径的中心代谢物，可以由两种关键酶（吲哚胺 2,3-双加氧酶和色氨酸 2,3-双加氧酶）产生，并且是最近公认的芳基烃的内源配体。受体（AHR），一种重要的细胞周期调节因子，其激活在肿瘤进展和免疫抑制中发挥作用。导致针对肿瘤色氨酸到犬尿氨酸代谢（可以被特定酶抑制剂阻断）和/或调节 AHR 介导的转录的新治疗方法我们还将评估通过 PET 估计的 AMT 代谢率，作为肿瘤的成像标记物。这将有助于监测新兴抑制剂的临床试验中的治疗反应。