Quantitative molecular MR-PET imaging of glycolysis in glioblastoma

胶质母细胞瘤糖酵解的定量分子 MR-PET 成像

• 批准号: 10638006
• 负责人: Benjamin M. Ellingson
• 金额: $ 61.9万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-10 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638006
• 关键词: Acidity; Amines; Behavior; Bioenergetics; Biological; Biopsy; Biopsy Specimen; Blood flow; Brain; Brain Neoplasms; Cell Density; Cells; Chemicals; Clinical; Collaborations; Data; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Early Diagnosis; Echo-Planar Imaging; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Exhibits; GLUT-3 protein; Gene Expression; Genetic Transcription; Glioblastoma; Glucose; Glycolysis; Human; Image; Image Guided Biopsy; Immunohistochemistry; Inferior; Isocitrate Dehydrogenase; Lactic acid; Magnetic Resonance Imaging; Malignant Neoplasms; Measurement; Measures; Medical; Metabolic; Metabolic Pathway; Molecular; Monitor; Mutate; Mutation; Oncogenes; Oncogenic; Oxidative Phosphorylation; Oxygen; Oxygen Consumption; Pathway interactions; Patients; Pentosephosphate Pathway; Perfusion; Phase I Clinical Trials; Phosphorylation; Positron-Emission Tomography; Predisposition; Production; Receptor Inhibition; Recurrence; Signal Transduction; Signal Transduction Pathway; Specificity; TP53 gene; Techniques; Therapeutic; Tissues; Tumor Suppressor Proteins; Tumor Tissue; Work; behavioral response; brain tissue; candidate marker; clinical imaging; design; extracellular; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; glucose metabolism; glucose uptake; hexokinase; imaging biomarker; imaging system; indexing; insight; novel; patient derived xenograft model; perfusion imaging; pharmacologic; prospective; protein expression; response; standard of care; targeted treatment; theories; therapeutic target; transcriptome sequencing; treatment response; tumor; uptake

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.

项目摘要/摘要 胶质母细胞瘤(GBM)是一种几乎没有临床选择的致命疾病。我们实验室的最新工作和 其他研究表明，由致癌驱动因素和肿瘤丢失引起的异常信号转导 抑制物，导致基底膜糖酵解通量增加。相应地，抑制致癌信号或 使用靶向治疗的下游信号转导通路可以诱导快速和特异性的改变 糖酵解，导致肿瘤能量和生物合成能力降低，使肿瘤容易进一步 治疗性利用。这种成像生物标记物将有助于提供对葡萄糖的独特洞察 新陈代谢和行为，使临床医生能够识别并最终利用潜在的治疗脆弱性。 而18F-脱氧葡萄糖(18F-FDG)PET显像是糖酵解显像的一个明显的候选生物标志物 由于它在其他癌症中普遍用于监测肿瘤的代谢行为和治疗反应，18F-FDG PET摄取量是衡量整体葡萄糖利用的指标，而不是专门的糖酵解。为了克服这种模棱两可 并为糖酵解提供了更高的特异性，我们建议将护理标准18F-FDG PET与快速pH相结合 氧敏胺化学交换饱和转移自旋梯度回波平面成像 (CEST-SAGE-EPI)，一种可以根据乳酸和氧气估计酸度的分子磁共振技术 使用，以及灌注和弥散磁共振，以说明血流量/体积和细胞密度的影响。 我们假设结合18F-FDGPET、胺CEST-SAGE-EPI、灌注MRI和弥散磁共振成像来创建 “糖酵解指数”，或称GI，将使我们能够准确地量化不同类型肿瘤内的糖酵解流量。 广泛可用的临床成像系统，用于研究葡萄糖代谢和对各种 人肾小球系膜的靶向治疗。 目前的研究将调查以下中心假设：(目标1)活检的肿瘤组织经历高密度脂蛋白。 可以可靠地检测通过RNA表达、蛋白质表达和生物能量学分析的糖酵解水平， 与组织酸碱度的直接测量相关，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和弥散磁共振成像；(AIM 2) 这种“糖酵解指数”可以通过使用脑部渗透性EGFR抑制剂干扰糖代谢来检测。 专为GBM设计，与药物改变和糖酵解信号改变相关 在IDH野生型患者中，EGFR扩增了GBM。