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，被认为是人类最致命的癌症之一。中位生存时间为14.6个月，在最积极的治疗方案后约25%的患者存活2年，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被广泛表征，并且已经出现了涉及胶质母细胞瘤生长和存活的关键癌症途径的重要框架，主要集中在RAS/MAPK途径的激活和PI 3激酶途径的失调上。然而，在胶质母细胞瘤患者中靶向抑制这些和其他分子途径在很大程度上是无效的，因此，人们越来越感兴趣地了解代谢改变的机制，因为它代表了相互作用以影响细胞生长和存活的基因突变星座的“功能读数”。胶质母细胞瘤的特征性和明确的代谢特征-FDG-PET上的强烈葡萄糖摄取、丰富的乳酸产生和NADP+依赖性异柠檬酸脱氢酶缺陷-可能是由于特定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中基因型-代谢表型相关的基本问题，我们聘请了一个多学科的医生和科学家团队进行临床和转化研究，旨在确定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。在目标1中，我们将通过在输注[U-13 C]葡萄糖或[1，2 - 13 C]葡萄糖后对遗传特征肿瘤进行13 C NMR光谱分析，分别评估柠檬酸循环中交叉的途径和通过磷酸戊糖途径的相对通量，来定义新型人原位小鼠模型中胶质母细胞瘤的代谢表型。具体来说，我们将确定胶质母细胞瘤的FDG特征-增加的葡萄糖摄取-是否正在喂养三种途径中的一种或某种组合：过量的无氧糖酵解为乳酸，过量的有氧糖酵解为丙酮酸，然后在柠檬酸循环中氧化，或通过戊糖磷酸途径的过量流量，以支持增殖或补偿IDH-1突变引起的NADPH产生损失。在目标2中，我们将定义胶质母细胞瘤患者的代谢表型，这些患者因假定的高级别胶质瘤而接受手术切除。在每例患者中，术中输注[U-13 C]葡萄糖或[1，2 - 13 C]葡萄糖后将获得肿瘤提取物的13 C NMR光谱分析。结果将与术前FDG-PET成像、7 T磁体上的超高分辨率MR成像、扩散张量成像和1H光谱学相关联，以生成肿瘤的全面非侵入性视图，目的是识别脑内的浸润性代谢活性肿瘤细胞。 公共卫生相关性：胶质母细胞瘤是最常见的原发性脑肿瘤，被认为是人类最致命的癌症之一。细胞的代谢比正常细胞高得多，并且像许多癌症一样，代表了癌症治疗中新药的可能靶点。我们提出的研究将剖析胶质母细胞瘤中异常的代谢途径，以共同努力快速开发新的疗法。

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.