Genotype and Metabolic Phenotype in Glioblastoma

描述（由申请人提供）：胶质母细胞瘤是成人中最常见的原发性脑肿瘤，被认为是最致命的人类癌症之一。在最积极的治疗方案后，中位生存时间为14.6个月，约25%的患者在2年后仍存活，显然迫切需要提高对胶质母细胞瘤基本生物学过程的理解。这种疾病背后的分子畸变已经被广泛表征，并且已经出现了参与胶质母细胞瘤生长和存活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通路的失调上。然而，在胶质母细胞瘤患者中，对这些和其他分子途径的靶向抑制在很大程度上是无效的，因此，人们对理解代谢改变的机制越来越感兴趣，因为它代表了相互作用影响细胞生长和存活的基因突变的“功能读出”。胶质母细胞瘤的特征和成熟的代谢特征- FDG-PET上强烈的葡萄糖摄取，丰富的乳酸产生和NADP+依赖性异柠檬酸脱氢酶的缺陷-可能是由于特定的基因突变而相互关联的事件。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。为了解决胶质母细胞瘤中基因型-代谢表型相关的基本问题，我们已经与一个由医生和科学家组成的多学科团队进行了一项临床和转化研究，旨在确定在体内脑微环境中驱动不受调节的肿瘤细胞增殖的关键代谢途径。在Aim 1中，我们将通过对输注[U-13C]葡萄糖或[1,2-13C]葡萄糖后的遗传特征肿瘤的13C NMR谱分析，在一个新的人类原位小鼠模型中定义胶质母细胞瘤的代谢表型，分别评估在柠檬酸循环中相交的途径和通过戊糖磷酸盐途径的相对通量。具体来说，我们将确定胶质母细胞瘤的FDG特征——葡萄糖摄取增加——是否提供了三种途径中的一种或几种组合：过量的厌氧糖酵解生成乳酸，过量的有氧糖酵解生成丙酮酸，然后在柠檬酸循环中氧化，或者通过戊糖磷酸途径的过量通量来支持增殖或补偿由于IDH-1突变导致的NADPH产生的损失。在Aim 2中，我们将定义为高度胶质瘤而接受手术切除的胶质母细胞瘤患者的代谢表型。每位患者术中输注[U-13C]葡萄糖或[1,2-13C]葡萄糖后，获得肿瘤提取物的13C NMR谱分析。结果将与术前FDG-PET成像、7T超高分辨率磁共振成像、弥散张量成像和1h光谱成像相关联，生成肿瘤的全面无创视图，目的是识别脑内浸润性、代谢活跃的肿瘤细胞。

DESCRIPTION (provided by applicant): 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.