Tryptophan metabolism in human brain tumors

描述(申请人提供)：尽管诊断和治疗方法有所改进，但脑瘤患者的预后仍然很差。我们研究的总体目标，正如在这次续期拨款申请中所概述的那样，是通过利用与色氨酸代谢肿瘤异常相关的机制来改善人类脑肿瘤的诊断和治疗。在第一次资助期间，我们使用核素放射示踪剂[11C]-甲基-L-色氨酸(AMT)的分子成像来检测和鉴别新诊断和复发的胶质瘤。AMT与其他几种氨基酸PET示踪剂的不同之处在于，AMT不是被结合到蛋白质中，而是通过免疫抑制犬尿氨酸途径代谢，该途径在各种癌症中上调。利用AMT示踪动力学分析，我们能够估计肿瘤的增殖活性，区分低级别胶质瘤类型，并区分复发胶质瘤和放射损伤。在联合配准的融合的PET/MRI图像上，我们还观察到AMT在肿瘤浸润性脑组织中的积聚，超出了MRI检测到的肿块。这与胶质瘤细胞不同程度地从实体瘤块渗入周围脑实质的观点是一致的。在我们初步数据的基础上，在拟议研究的目标1中，我们将使用在PET上非侵入性测量的AMT积聚程度作为肿瘤浸润性脑实质中肿瘤细胞密度的替代标记。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手术后肿瘤复发的预测因素；我们还将通过AMT摄取特征来区分原发胶质瘤和常见的脑转移瘤。在目标2中，我们将评估恶性星形细胞胶质瘤术后化疗患者的定量AMT PET和灌注MRI的准确性，以区分早期肿瘤进展(最初治疗后6个月)和假性进展，这是最近出现的临床难题。我们还将测试这些神经成像技术在预测晚期(&gt；6个月)肿瘤复发的时间和位置以及在常规MRI出现进展迹象之前的存活率方面的价值。在目标3中，我们将研究从胶质瘤和常见的脑转移瘤中获得的肿瘤样本中色氨酸代谢的机制。我们将集中于肿瘤犬尿氨酸的组织病理学和影像相关性，犬尿氨酸途径的中心代谢物。犬尿氨酸可以由两种关键酶(吲哚胺2，3-双加氧酶和色氨酸2，3-双加氧酶)产生，是新近发现的芳基碳氢受体(AHR)的内源性配体，AHR是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。预期的结果将导致针对肿瘤色氨酸到犬尿氨酸代谢(可以被特定的酶抑制剂阻断)和/或调节AHR介导的转录的新的治疗方法。我们还将评估AMT代谢率，由PET估计，作为肿瘤免疫抑制的成像标志。这将有助于在新出现的抑制剂的临床试验中监测治疗反应。

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.