IMAGING TELOMERE MAINTENANCE MECHANISMS IN GLIOMAS

项目总结 所有肿瘤，包括胶质瘤，都需要端粒维持机制(TMM)，以便 因此，TMM无限增殖，被认为是癌症的标志。主要 胶质母细胞瘤和低级别少突胶质细胞瘤使用端粒酶逆转录酶的重新激活 转录酶(TERT)表达作为其TMM，而低级别星形细胞瘤使用替代 端粒(ALT)通路延长。由于它们的本质，TERT和ALT是 有吸引力的治疗靶点，有趣的是，研究表明抑制TERT可以导致 通过诱导ALT途径产生的抗性。我们的目标是识别新奇的、磁共振的 光谱学(MRS)-胶质瘤中TERT和ALT的可检测代谢生物标记物 实现肿瘤负担和治疗反应的非侵入性成像。我们的科学前提 先前的研究和我们的初步数据表明，TERT和ALT是相关的 具有显著的代谢重新编程，导致独特的MRS可检测的代谢 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状态的成像生物标记物 和患者来源的胶质瘤细胞；目标2-确定1H-和超极化13C-的用途- MRS用于体内原位胶质瘤移植瘤TMM状态的代谢成像；目标3：至 通过确定分子机制来机械地验证我们的成像生物标记物 TERT和ALT改变了胶质瘤的代谢。这项建议的创新之处在于：1) 尽管TMM与新陈代谢重新编程有关，但我们是第一个提出利用 这种非侵入性成像的链接2)我们可以访问独特的基因工程和患者- 不同TMM状态的衍生胶质瘤模型3)我们建议使用无偏原理 成分分析，以确定TMM相关的代谢改变和4)我们可以访问和 在应用创新的平移超极化13C-MRS成像方法方面的专业知识 到脑瘤。这项研究具有重要意义，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成像手段，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脑组织、水肿或坏死区分开来。 并监测肿瘤复发和对化疗或放射治疗的反应。身份识别 针对TMM状态量身定做的成像生物标记物也将允许检测肿瘤对新技术的反应 TMM抑制剂与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，我们的成像生物标记物也可能被应用于 胶质瘤以外的其他肿瘤类型。

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.