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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要胶质母细胞瘤（GBM）是一种致命的疾病，我们的实验室和最近的临床研究很少。其他人表明，异常信号转导源自致癌驱动因素和肿瘤丧失抑制剂，导致GBM中令人惊叹的糖酵解通量，相应地，抑制致癌信号或。使用靶向治疗的下游信号转导途径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，使肿瘤容易受到进一步的影响这种成像生物标志物对于提供对葡萄糖的独特洞察具有治疗作用。新陈代谢和行为，使忠诚者能够识别并最终利用潜在的治疗漏洞。 18F-氟脱氧葡萄糖 (18F-FDG) PET 成像是糖酵解成像的明显候选生物标志物由于它在其他癌症中广泛用于监测肿瘤代谢行为和治疗反应，18F-FDG PET 摄取是衡量总体葡萄糖利用率的指标，而不是专门针对糖酵解的指标。并为糖酵解提供更多特异性，我们建议将护理标准 18F-FDG PET 与快速 pH 相结合和氧敏感胺化学交换饱和度转移自旋梯度回波回波平面成像 (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 来解释血流/体积和细胞密度的影响。我们结合 18F-FDG PET、胺 CEST-SAGE-EPI、灌注 MRI 和扩散 MRI 来创建 “糖酵解指数”（GI）将使我们能够准确量化异质肿瘤内的糖酵解通量广泛使用的临床成像系统，用于研究葡萄糖代谢和对各种疾病的反应人类 GBM 的靶向治疗。当前的研究将调查中心假设：（目标 1）对肿瘤组织进行活检，进行高通过 RNA 表达、蛋白质表达和生物能量学可以可靠地检测糖酵解水平，分析与组织 pH 值的直接测量相关，并与“糖酵解指数”密切相关结合 18F-FDG PET、胺 CEST-SAGE-EPI、灌注 MRI 和扩散 MRI；以及（目标 2）变化；这种“糖酵解指数”可以通过使用脑渗透性 EGFR 抑制剂扰乱葡萄糖代谢来检测专为 GBM 设计，与药理学改变和糖酵解信号传导改变相关在 IDH 野生型患者中，EGFR 扩增 GBM。