Quantitative molecular MR-PET imaging of glycolysis in glioblastoma

项目总结/摘要 胶质母细胞瘤（GBM）是一种一致致命的疾病，临床选择很少。我们实验室最近的工作， 其他研究表明，源自致癌驱动因子和肿瘤丢失的异常信号转导 抑制剂，导致GBM中糖酵解通量增加。相应地，抑制致癌信号传导或 使用靶向治疗的下游信号转导途径可以诱导细胞内的快速和特异性改变， 糖酵解，导致肿瘤能量和生物合成能力降低，使肿瘤容易受到进一步的破坏。 治疗性剥削这种成像生物标志物将有助于提供对葡萄糖的独特见解 代谢和行为，使临床医生能够识别并最终利用潜在的治疗漏洞。 而18 F-氟脱氧葡萄糖（18 F-FDG）PET显像是糖酵解显像的明显候选生物标志物 由于18F-FDG在其他癌症中广泛用于监测肿瘤代谢行为和治疗反应， PET摄取是总体葡萄糖利用的量度，而不是特别是糖酵解。为了克服这种模糊性 为糖酵解提供更多的特异性，我们建议将护理标准18F-FDG PET与快速pH 和氧敏胺化学交换饱和转移自旋梯度回波平面回波成像 （CEST-SAGE-EPI），一种分子MRI技术，可以估计乳酸和氧气的酸度 利用，以及灌注和扩散MRI，以说明血流/体积和细胞密度的影响。 我们假设结合18F-FDG PET、胺CEST-SAGE-EPI、灌注MRI和弥散MRI， “糖酵解指数”或GI将使我们能够准确地量化异质性肿瘤中的糖酵解通量， 用于研究葡萄糖代谢和对各种疾病的反应的广泛可用的临床成像系统 在人类GBM中的靶向治疗。 当前的研究将调查中心假设：（目的1）活检的肿瘤组织经历了高强度的生长。 通过RNA表达、蛋白质表达和生物能量学分析可以可靠地检测糖酵解水平， 与组织pH值的直接测量相关，并与由以下因素产生的“糖酵解指数”密切相关： 结合18F-FDG PET、胺CEST-SAGE-EPI、灌注MRI和弥散MRI;以及（目的2） 这种“糖酵解指数”可以通过使用脑渗透EGFR抑制剂干扰葡萄糖代谢来检测 专为GBM设计，并与药理学改变和糖酵解信号传导的改变相关 在IDH野生型患者中，EGFR扩增GBM。

PROJECT SUMMARY/ABSTRACT Glioblastoma (GBM) is a uniformly fatal disease with very few clinical options. Recent work from our lab and others indicates that abnormal signal transduction, originating from oncogenic drivers and loss of tumor suppressors, results in heightened glycolytic flux in GBM. Correspondingly, inhibition of oncogenic signaling or downstream signal transduction pathways using targeted therapies can induce rapid and specific alterations in glycolysis, resulting in reduced tumor energetic and biosynthetic capacity, making the tumor vulnerable to further therapeutic exploitation. Such an imaging biomarker would be useful for providing unique insight into glucose metabolism and behavior, allowing clinicians to identify and ultimately exploit potential therapeutic vulnerabilities. While 18F-fluorodeoxyglucose (18F-FDG) PET imaging is an obvious candidate biomarker for imaging glycolysis as it is used ubiquitously in other cancers to monitor tumor metabolic behavior and treatment response, 18F-FDG PET uptake is a measure of overall glucose utilization, not specifically glycolysis. To overcome this ambiguity and provide more specificity for glycolysis, we propose combining standard of care 18F-FDG PET with fast pH and oxygen-sensitive amine chemical exchange saturation transfer spin-and-gradient-echo echoplanar imaging (CEST-SAGE-EPI), a molecular MRI technique that can estimate both acidity from lactic acid and oxygen utilization, as well as perfusion and diffusion MRI to account for the effects of blood flow/volume and cell density. We hypothesize combining 18F-FDG PET, amine CEST-SAGE-EPI, perfusion MRI, and diffusion MRI to create a “glycolytic index”, or GI, will allow us to accurately quantify glycolytic flux within heterogeneous tumors on widely available clinical imaging systems for use in studying glucose metabolism and response to a variety of targeted therapies in human GBM. The current study will investigate the central hypotheses that: (Aim 1) biopsied tumor tissue undergoing high levels of glycolysis via RNA expression, protein expression, and bioenergetics analyses can be reliably detected, correlates with direct measure of tissue pH, and strongly associated with a “glycolytic index” created by combining 18F-FDG PET, amine CEST-SAGE-EPI, perfusion MRI and diffusion MRI; and (Aim 2) changes in this “glycolytic index” can be detected by perturbing glucose metabolism using a brain penetrant EGFR inhibitor specifically designed for GBM and correlate with pharmacologic alterations and alterations in glycolytic signaling in patients with IDH wild-type, EGFR amplified GBM.