Project 3: Metabolic imaging of TERT expression

项目3：TERT表达的代谢成像

基本信息

批准号：
10020343
负责人：
Sabrina Miriam Ronen
金额：
$ 40.3万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10020343
关键词：
6-phosphogluconate Acetoacetates Address Adenine Nucleotides Ascorbic Acid Aspartate Biological Markers Brain Neoplasms Cell Extracts Cell Line Cell Nucleus Cell Proliferation Cell physiology Cells Clinic Data Development Engineering Genetic Glioblastoma Glioma Glucose Glutathione Glutathione Disulfide Goals Image Implant Induced Mutation Lead Link Magnetic Resonance Spectroscopy Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Monitor Mutation NADP Outcome Oxidation-Reduction Oxides Patients Pentosephosphate Pathway Pharmacology Phenotype Process RNA-Directed DNA Polymerase Reaction Reactive Oxygen Species Recurrence Reporting Research Reverse Transcriptase Inhibitors Role Signal Pathway Small Interfering RNA Somatic Cell Telomerase Telomerase inhibition Testing Therapeutic Treatment Efficacy Treatment outcome base beta-Hydroxybutyrate brain parenchyma cancer cell care outcomes drug development genetically modified cells imaging approach imaging biomarker imaging modality improved improved outcome in vivo inhibitor/antagonist innovation metabolic imaging molecular subtypes mouse model neoplastic cell new therapeutic target non-invasive imaging non-invasive monitor novel oligodendroglioma personalized care promoter telomere tumor virtual

项目摘要

ABSTRACT Telomerase reverse transcriptase (TERT) enables telomere elongation that is essential for continuous cell proliferation. TERT expression that is associated with activating mutations in the TERT promoter, is observed in virtually all glioblastoma and oligodendroglioma cases. This makes TERT the most common genetic alteration in brain tumors, and a novel therapeutic target. Noninvasive imaging of TERT expression could therefore help in distinguishing between pseudo-progression and recurrent glioma, and provide a noninvasive biomarker for assessment of treatment efficacy by TERT inhibitors. However, to date, no translational imaging approaches for TERT expression have been reported. The goal of Project 3 is to address this critical need by developing metabolic imaging biomarkers of TERT expression. Our approach is based on previous reports showing that TERT expression is associated with control of cellular redox, and our preliminary data confirming this finding and identifying additional metabolic alterations. Specifically, we have found that 1H magnetic resonance spectroscopy (MRS)-detectable levels of glutathione and the 13C MRS-detectable metabolism of hyperpolarized dehydroxyascorbate to vitamin C, are elevated in TERT-expressing cells. Additionally, hyperpolarized 13C MRS- detectable fluxes of glucose and gluconolactone via the pentose phosphate pathway to 6-phosphogluconate are elevated, as are the levels of aspartate and adenosine phosphates. We therefore hypothesize that advanced MRS metabolic imaging could be used to distinguish glioma cells expressing TERT from normal brain parenchyma and from tumor cells in which TERT expression is silenced by treatment. We will test this hypothesis as follows. In Aim 1 we will identify 1H MRS and hyperpolarized 13C MRS metabolic imaging biomarkers that are associated with TERT expression by investigating cell lines that differ only in their TERT status and determining if levels of MRS-detectable metabolic biomarkers associated with redox, and other metabolic changes can distinguish TERT-expressing from TERT non-expressing cells. In Aim 2 we will determine whether MRS- detectable biomarkers of redox can be used to monitor TERT expression in vivo by using mouse models with orthotopic TERT-expressing brain tumors, inhibiting TERT expression via genetic and/or pharmacological approaches, and determining if this inhibition can be assessed using 1H and/or hyperpolarized 13C MRS biomarkers of redox. If cell studies show that other metabolic pathways are modulated by TERT, these will also be investigated in vivo. In Aim 3 we will investigate mechanisms linking TERT expression with metabolism by assessing cellular processes known to be associated with TERT expression and determining if these processes are mechanistically linked to changes in redox-associated metabolic pathways or other MRS-detectable metabolic pathways altered by TERT. Our study is expected to lead to translatable MRS-detectable metabolic biomarkers of TERT expression that could improve glioma patient treatment and outcome.

抽象的端粒酶逆转录酶 (TERT) 能够延长端粒，这对于连续细胞至关重要增殖。 TERT 表达与 TERT 启动子中的激活突变相关，在几乎所有胶质母细胞瘤和少突胶质细胞瘤病例。这使得 TERT 成为最常见的基因改变脑肿瘤，以及一个新的治疗靶点。因此，TERT 表达的无创成像可能会有所帮助区分假性进展和复发性胶质瘤，并提供非侵入性生物标志物 TERT抑制剂的治疗效果评估。然而，迄今为止，还没有平移成像方法 TERT 表达已有报道。项目 3 的目标是通过开发来满足这一关键需求 TERT 表达的代谢成像生物标志物。我们的方法基于之前的报告，表明 TERT 表达与细胞氧化还原的控制相关，我们的初步数据证实了这一发现识别额外的代谢改变。具体来说，我们发现 1H 磁共振波谱 (MRS)-可检测的谷胱甘肽水平和 13C MRS-可检测的超极化代谢脱羟基抗坏血酸转化为维生素 C，在 TERT 表达细胞中升高。此外，超极化 13C MRS- 通过磷酸戊糖途径生成 6-磷酸葡萄糖酸的葡萄糖和葡萄糖酸内酯的可检测通量为升高，天冬氨酸和磷酸腺苷的水平也升高。因此我们假设先进的 MRS代谢成像可用于区分表达TERT的神经胶质瘤细胞与正常大脑实质上和肿瘤细胞中 TERT 表达因治疗而沉默。我们将检验这个假设如下。在目标 1 中，我们将识别 1H MRS 和超极化 13C MRS 代谢成像生物标志物，它们是通过研究仅 TERT 状态不同的细胞系并确定与 TERT 表达相关的如果 MRS 可检测到的与氧化还原和其他代谢变化相关的代谢生物标志物的水平可以区分 TERT 表达细胞和 TERT 非表达细胞。在目标 2 中，我们将确定 MRS- 可检测的氧化还原生物标志物可用于通过使用小鼠模型来监测体内 TERT 表达原位表达 TERT 的脑肿瘤，通过遗传和/或药理学抑制 TERT 表达方法，并确定是否可以使用 1H 和/或超极化 13C MRS 来评估这种抑制氧化还原生物标志物。如果细胞研究表明其他代谢途径受到 TERT 的调节，那么这些途径也将受到 TERT 的调节。进行体内研究。在目标 3 中，我们将通过以下方式研究 TERT 表达与代谢的联系机制：评估已知与 TERT 表达相关的细胞过程并确定这些过程是否与氧化还原相关代谢途径或其他 MRS 可检测的变化在机制上相关 TERT 改变代谢途径。我们的研究预计将导致可翻译的 MRS 可检测的代谢 TERT 表达的生物标志物可以改善神经胶质瘤患者的治疗和结果。