Tryptophan Metabolism in Human Brain Tumors

描述（由申请人提供）：脑肿瘤是美国每年大约13,000人死亡的原因，这些肿瘤代表了儿童中最常见的实体肿瘤类型。近年来的研究表明，诱导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），这是犬尿氨酸途径的限速步骤。我们使用示踪剂1-[11C]甲基- l-色氨酸（AMT）的正电子发射断层扫描（PET）进行的初步研究显示，不同脑肿瘤中AMT的摄取和代谢以及切除肿瘤组织中IDO的表达均有差异增加。这些数据表明，AMT在这些肿瘤中的积累与通过犬尿氨酸途径增加色氨酸代谢有关。该应用程序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，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免疫反应性和切除肿瘤组织中的多药耐药（MDR）蛋白联系起来。本研究提出三个目的：(i)建立AMT PET术前对脑肿瘤与非肿瘤病变的鉴别，初步治疗后对残留或复发肿瘤的检测，以及对复发肿瘤与放射性坏死的鉴别。（ii）基于AMT的运输和代谢捕获的测量来区分不同类型的脑肿瘤。（iii）确定PET成像所得AMT动力学参数与肿瘤组织组织学分析所得肿瘤增殖指数、IDO、多药耐药蛋白表达之间的关系。这些研究将利用体内分子成像与AMT PET和体外肿瘤组织研究相结合的创新方法，阐明色氨酸异常摄取和代谢的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成像对原发性和残余/复发性脑肿瘤的应用，这对准确诊断仍然是一个重大挑战。这一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，并有可能开发出以色氨酸代谢和MDR蛋白为靶点的脑肿瘤药物治疗新策略。本项目将脑肿瘤的PET成像与示踪剂1-[11C]甲基- l-色氨酸结合，并在体外分析切除脑肿瘤组织中免疫调节酶吲哚胺2,3-双加氧酶（IDO）以及多种多药耐药（MDR）蛋白的表达。该发现将为原发性和复发性脑肿瘤的诊断提供改进，也将为脑肿瘤中色氨酸代谢异常的机制提供新的见解，并有可能开发出以色氨酸代谢和MDR蛋白为靶点的脑肿瘤药物治疗新策略。

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.