IMAGING TELOMERE MAINTENANCE MECHANISMS IN GLIOMAS

胶质瘤中端粒维持机制的成像

• 批准号: 10552020
• 负责人: Sabrina Miriam Ronen
• 金额: $ 65.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-11 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552020
• 关键词: ATRX gene; Alanine; Animals; Area; Astrocytoma; Biological; Biological Markers; Brain; Brain Neoplasms; Caring; Cell division; Cells; Cellular Metabolic Process; Clinical; Data; Dehydroascorbic Acid; Detection; Edema; Enzymes; GLUT-3 protein; Genes; Genetic Engineering; Genetic Transcription; Glioblastoma; Glioma; Glucose; Glutamates; Glutamine; Goals; Human; Image; Link; Magnetic Resonance Spectroscopy; Maintenance; Malignant Neoplasms; Metabolic; Metabolism; Modeling; Molecular; Monitor; Mutation; Nature; Necrosis; Nuclear; Outcome; PDH kinase; Pathway interactions; Patient-Focused Outcomes; Patients; Play; Principal Component Analysis; Proliferating; Proteins; Quality of life; RNA-Directed DNA Polymerase; Radiation therapy; Recurrent tumor; Reduced Glutathione; Research; Resistance; Resistance development; Reverse Transcriptase Inhibitors; Role; Somatic Cell; Structure; Telomerase; Telomerase Inhibitor; Telomerase inhibition; Telomere Capping; Telomere Maintenance; Telomere Pathway; Therapeutic; Tissues; Tumor Burden; Xenograft procedure; beta catenin; biomarker identification; cancer cell; chemotherapy; chromatin remodeling; cytochrome c oxidase; glioma cell line; glucose metabolism; homologous recombination; imaging biomarker; imaging modality; improved; in vivo; inhibitor; innovation; knock-down; lipid metabolism; longitudinal analysis; melanoma; metabolic imaging; non-invasive imaging; non-invasive monitor; novel; oligodendroglioma; personalized care; pharmacologic; response; telomere; therapeutic target; tool; treatment response; tumor

PROJECT SUMMARY All tumors, including gliomas, need a telomere maintenance mechanism (TMM) in order to proliferate indefinitely and TMMs are, therefore, considered hallmarks of cancer. Primary glioblastomas and low-grade oligodendrogliomas use reactivation of telomerase reverse transcriptase (TERT) expression as their TMM while low-grade astrocytomas use the alternative lengthening of telomeres (ALT) pathway. Due to their essential nature, TERT and ALT are attractive therapeutic targets and, interestingly, studies indicate that TERT inhibition can lead to resistance by induction of the ALT pathway. Our goal is to identify novel, magnetic resonance spectroscopy (MRS)-detectable metabolic biomarkers of TERT and ALT in gliomas that will enable non-invasive imaging of tumor burden and response to therapy. Our scientific premise is that prior studies as well as our preliminary data, indicate that TERT and ALT are associated with significant metabolic reprogramming, resulting in unique MRS-detectable metabolic signatures of TMM status. Our specific aims are as follows: Aim 1- to identify non-invasive 1H- and hyperpolarized 13C-MRS-based imaging biomarkers of TMM status in genetically-engineered and patient-derived glioma cells; Aim 2- to determine the utility of 1H- and hyperpolarized 13C- MRS for metabolic imaging of TMM status in orthotopic glioma xenografts in vivo; Aim 3: to mechanistically validate our imaging biomarkers by identifying the molecular mechanisms by which TERT and ALT alter metabolism in gliomas. This proposal is innovative because: 1) although TMM have been linked to metabolic reprogramming, we are the first to propose to exploit this link for non-invasive imaging 2) we have access to unique genetically-engineered and patient- derived glioma models that differ in TMM status 3) we propose to use unbiased principal component analysis to identify TMM-linked metabolic alterations and 4) we have access to and expertise in the application of innovative, translational hyperpolarized 13C-MRS imaging methods to brain tumors. This research is significant because the metabolic biomarkers identified here will provide a non-invasive means of imaging TMMs, which are molecular features of brain tumors. This will enable clinicians to distinguish tumor from regions of normal brain, edema or necrosis and to monitor tumor recurrence and response to chemotherapy or radiotherapy. Identification of imaging biomarkers tailored to TMM status will also allow detection of tumor response to novel TMM inhibitors and the development of resistance to TMM inhibitors. Importantly, since TMMs are a universal hallmark of cancer, our imaging biomarkers can potentially also be applied to tumor types other than gliomas.

项目摘要 所有肿瘤，包括神经胶质瘤，都需要一种端粒维护机制（TMM）才能 因此，无限期增殖，TMM被认为是癌症的标志。基本的 胶质母细胞瘤和低度寡聚胶质瘤使用端粒酶反向激活 低级星形瘤使用替代方案，转录酶（TERT）作为其TMM的表达 端粒（ALT）途径的延长。由于其本质，Tert和Alt是 有吸引力的治疗靶标，有趣的是，研究表明，TERT抑制作用可能导致 通过诱导ALT途径的抗性。我们的目标是确定新颖的磁共振 光谱（MRS） - 可探望的胶质瘤中TERT和ALT的代谢生物标志物，将 使肿瘤负担的无创成像和对治疗的反应。我们的科学前提 是先前的研究以及我们的初步数据，表明TERT和ALT是相关的 具有明显的代谢重编程，从而产生独特的MRS可检测代谢 TMM状态的签名。我们的具体目的如下：目标1-确定非侵入性1H- 和基于超极化的13C-MRS成像生物标志物的TMM状态遗传工程 和患者来源的神经胶质瘤细胞；目标2-确定1H和超极化13C-的效用 MRS用于体内原位神经胶质瘤异种移植物中TMM状态的代谢成像；目标3：到 通过机械学来验证我们的成像生物标志物，通过识别分子机制 tert和alt改变了神经胶质瘤中的代谢。该提议具有创新性，因为：1） 尽管TMM已与代谢重编程相关，但我们是第一个提议利用的人 这种非侵入性成像的链接2）我们可以访问独特的遗传工程和患者 - TMM状态不同的派生神经瘤模型3）我们建议使用公正的主体 组件分析以识别TMM链接的代谢改变，4）我们可以访问和 在应用创新的，转化超极化的13c-MRS成像方法方面的专业知识 到脑肿瘤。这项研究很重要，因为这里确定的代谢生物标志物 将提供非侵入性成像TMM的方法，这是脑肿瘤的分子特征。 这将使临床医生能够将肿瘤与正常大脑，水肿或坏死区域区分开 并监测肿瘤复发和对化学疗法或放疗的反应。识别 成像针对TMM状态量身定制的生物标志物也将允许检测到对新型的肿瘤反应 TMM抑制剂和对TMM抑制剂的耐药性的发展。重要的是，由于TMM 是癌症的普遍标志，我们的成像生物标志物也可以应用于 除神经胶质瘤以外的肿瘤类型。