IMAGING TELOMERE MAINTENANCE MECHANISMS IN GLIOMAS

胶质瘤中端粒维持机制的成像

基本信息

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
项目类别：
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

项目摘要

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.

项目概要所有肿瘤，包括神经胶质瘤，都需要端粒维持机制 (TMM) TMM 无限增殖，因此被认为是癌症的标志。基本的胶质母细胞瘤和低级别少突胶质细胞瘤利用端粒酶逆转的重新激活转录酶 (TERT) 表达作为其 TMM，而低级别星形细胞瘤则使用替代方案端粒（ALT）途径延长。由于其本质性质，TERT 和 ALT 是有吸引力的治疗靶点，有趣的是，研究表明 TERT 抑制可以导致通过诱导 ALT 途径产生耐药性。我们的目标是识别新颖的磁共振光谱学 (MRS) - 可检测神经胶质瘤中 TERT 和 ALT 的代谢生物标志物实现肿瘤负荷和治疗反应的非侵入性成像。我们的科学前提之前的研究以及我们的初步数据表明 TERT 和 ALT 相关具有显着的代谢重编程，产生独特的 MRS 可检测代谢 TMM 状态的签名。我们的具体目标如下：目标 1- 识别非侵入性 1H- 和基于超极化 13C-MRS 的基因工程 TMM 状态成像生物标志物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 用于体内原位胶质瘤异种移植物 TMM 状态的代谢成像；目标 3：通过识别分子机制来机械地验证我们的成像生物标志物其中 TERT 和 ALT 改变神经胶质瘤的代谢。该提议具有创新性，因为：1）尽管 TMM 与代谢重编程有关，但我们是第一个提出利用此链接用于非侵入性成像 2) 我们可以获得独特的基因工程和患者- 衍生出 TMM 状态不同的神经胶质瘤模型 3) 我们建议使用无偏原则成分分析来识别 TMM 相关的代谢改变，4) 我们可以访问和创新、平移超极化 13C-MRS 成像方法应用方面的专业知识到脑肿瘤。这项研究意义重大，因为这里确定的代谢生物标志物将提供一种非侵入性的 TMM 成像方法，TMM 是脑肿瘤的分子特征。这将使临床医生能够区分肿瘤与正常大脑、水肿或坏死区域并监测肿瘤复发和对化疗或放疗的反应。鉴定针对 TMM 状态定制的成像生物标志物也将允许检测肿瘤对新药物的反应 TMM 抑制剂和 TMM 抑制剂耐药性的发展。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有可能应用于神经胶质瘤以外的肿瘤类型。