GENOTYPE AND METABOLIC PHENOTYPE IN GLIOBLASTOMA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 胶质母细胞瘤是成人最常见的原发脑瘤，被认为是人类最致命的癌症之一。在最激进的治疗方案后，中位生存期为14.6个月，大约25%的患者在两年内存活，显然迫切需要提高对胶质母细胞瘤基本生物学过程的了解。该疾病的分子异常已被广泛描述，并出现了与胶质母细胞瘤生长和生存有关的关键癌症通路的重要框架，主要集中在Ras/MAPK通路的激活和PI3Kinase通路的失调。然而，针对胶质母细胞瘤患者的这些和其他分子通路的靶向抑制在很大程度上是无效的，因此，人们对了解代谢改变的机制越来越感兴趣，因为它代表了一系列相互作用、影响细胞生长和生存的基因突变的功能读数。胶质母细胞瘤的特征和成熟的代谢特征-FDG-PET高摄取葡萄糖，大量乳酸产生，以及NADP+依赖的异柠檬酸脱氢酶缺陷-可能是由于特定的基因突变而导致的相互关联的事件。或者，这些特征可能是反映癌细胞遗传程序冗余的共同终点。为了解决与胶质母细胞瘤的基因型-代谢表型相关的基本问题，我们聘请了一个由医生和科学家组成的多学科团队进行临床和翻译研究，旨在确定在体内推动脑微环境中肿瘤细胞不受调控的增殖的关键代谢途径。在目标1中，我们将通过输注[U-13C]葡萄糖或[1，2-13C]葡萄糖后对具有遗传特征的肿瘤的13C核磁共振光谱分析，在一个新的人原位小鼠模型中定义胶质母细胞瘤的代谢表型，以分别评估在柠檬酸循环中相交的途径和通过戊糖磷酸途径的相对通量。具体地说，我们将确定胶质母细胞瘤的FDG特征-葡萄糖摄取增加-是否满足三种途径中的一种或三种途径的组合：过量的厌氧糖酵解为乳酸，过量的有氧糖酵解为丙酮酸，然后在柠檬酸循环中氧化，或者过量的通量通过戊糖磷酸途径支持增殖或补偿IDH-1突变导致的NADPH产生的损失。在目标2中，我们将确定高级别胶质瘤手术切除患者的代谢表型。在每个患者中，在术中输注[U-13C]葡萄糖或[1，2-13C]葡萄糖后，将获得肿瘤提取物的13C核磁共振波谱分析。结果将与FDG-PET的术前成像、7T磁体的超高分辨率磁共振成像、扩散张量成像和1H-波谱相关联，以生成肿瘤的全面非侵入性图像，目的是识别大脑内浸润性、代谢活跃的肿瘤细胞。公共卫生相关性：胶质母细胞瘤是最常见的原发脑肿瘤，被认为是人类最致命的癌症之一。细胞的新陈代谢比正常细胞高得多，像许多癌症一样，它代表着癌症治疗新药的一个可能靶点。我们提议的研究将剖析胶质母细胞瘤中异常的代谢途径，以共同努力迅速开发新的治疗方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Glioblastoma, the most common primary brain tumor in adults, is considered to be among the deadliest of human cancers. With a median survival time of 14.6 months and approximately 25% of patients alive at 2 years after the most aggressive treatment regimens, there is clearly a desperate need to improve the understanding of basic biological processes in glioblastoma. The molecular aberrations underlying this disease have been extensively characterized and an important framework of critical cancer pathways involved in glioblastoma growth and survival has emerged, centered prominently on activation of the RAS/MAPK pathway and dysregulation of the PI3Kinase pathway. However, targeted inhibition of these and other molecular pathways in glioblastoma patients has been largely ineffective and, as a result, there is increasing interest in understanding mechanisms of altered metabolism since it represents a 'functional readout' of the constellation of genetic mutations that interact to influence cell growth and survival. The characteristic and well established metabolic features of glioblastoma - intense glucose uptake on FDG-PET, abundant lactate production, and a defect in NADP+ - dependent isocitrate dehydrogenase - may be interconnected events due to a specific genetic mutation. Alternatively, these features may be a common endpoint reflecting redundancy in the cancer cell's genetic program. To address basic questions related to the genotype-metabolic phenotype connection in glioblastoma we have engaged a multidisciplinary team of physicians and scientists in a clinical and translational study designed to identify the critical metabolic pathways that drive unregulated tumor cell proliferation in the brain microenvironment in vivo. In Aim 1 we will define the metabolic phenotype of glioblastoma in a novel human orthotopic mouse model by 13C NMR spectral analysis of genetically characterized tumors following infusion of [U-13C]glucose or [1,2-13C]glucose to assess, respectively, the pathways intersecting in the citric acid cycle and relative flux through the pentose phosphate pathway. Specifically, we will determine whether the FDG signature of glioblastoma - increased glucose uptake - is feeding one or some combination of three pathways: excess anaerobic glycolysis to lactate, excess aerobic glycolysis to pyruvate followed by oxidation in the citric acid cycle, or excess flux through the pentose phosphate pathway to support proliferation or to compensate for loss of NADPH production due to mutation of IDH-1. In Aim 2 we will define the metabolic phenotype in glioblastoma patients undergoing surgical resection for presumed high grade glioma. In each patient, 13C NMR spectral analysis of tumor extracts will be obtained after intra-operative infusion of [U-13C]glucose or [1,2-13C]glucose. Results will be correlated with preoperative imaging by FDG-PET, ultra high resolution MR imaging on a 7T magnet, diffusion tensor imaging and 1H-spectroscopy to generate a comprehensive non-invasive view of the tumor with the goal of identifying infiltrative, metabolically active tumor cells within the brain. PUBLIC HEALTH RELEVANCE: Glioblastoma is the most common primary brain tumor and is considered to be among the deadliest of human cancers. The metabolism of the cells is much higher than normal cells and, like many cancers, represents a possible target for new drugs in cancer therapy. Our proposed research will dissect the metabolic pathways that are abnormal in glioblastoma in a concerted effort to develop new therapies quickly.