Tryptophan Metabolism in Human Brain Tumors

描述(申请人提供)：脑瘤是美国每年约13,000人的死因，是儿童最常见的实体肿瘤。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耐受的重要机制，主要是通过免疫调节酶吲哚-2，3-双加氧酶(IDO)来实现的，该酶是犬尿氨酸途径的限速步骤。我们用示踪剂1-[11C]甲基-L-色氨酸(AMT)进行正电子发射断层扫描的初步研究表明，不同脑肿瘤对AMT的摄取和代谢有不同程度的增加，切除的肿瘤组织中也有IDO的表达。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的代谢有关。这项申请将解决色氨酸在儿童和成人脑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AMT在不同脑肿瘤中的体内摄取和代谢，并将这些结果与肿瘤增殖指数、IDO免疫反应性和切除的肿瘤组织中的多药耐药(MDR)蛋白相关联。提出了三个目标：(1)建立AMT PET能够在术前鉴别脑肿瘤和非肿瘤病变，并在初次治疗后发现残留或复发的肿瘤，以及鉴别复发的肿瘤和放射性坏死。(Ii)根据AMT的转运和代谢陷阱的测量来区分不同类型的脑肿瘤。(3)研究肿瘤组织中多药耐药蛋白表达与肿瘤增殖指数、IDO及肿瘤组织多药耐药蛋白表达的关系。这些研究将采用体内分子成像、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，我们的研究将确定AMT PET成像在原发和残留/复发脑肿瘤中的应用，这仍然是准确诊断的主要挑战。这一发现将为脑肿瘤中色氨酸异常摄取和代谢的机制提供新的见解，并有可能通过靶向色氨酸代谢和MDR蛋白来开发利用药物治疗脑肿瘤的新策略。本项目结合脑肿瘤的正电子发射计算机断层扫描和示踪剂1-[11C]甲基-L-色氨酸，并在体外分析免疫调节酶吲哚胺2，3-双加氧酶以及各种多药耐药蛋白在切除的脑肿瘤组织中的表达。这一发现将改善对原发和复发脑肿瘤的诊断，还将为脑肿瘤色氨酸代谢异常的机制提供新的见解，并有可能通过靶向色氨酸代谢和MDR蛋白来开发利用药物治疗脑肿瘤的新策略。

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.