IMAGING TELOMERE MAINTENANCE MECHANISMS IN GLIOMAS

项目摘要 所有的肿瘤，包括神经胶质瘤，都需要端粒维持机制（TMM）， 无限期地增殖，因此，TGFs被认为是癌症的标志。初级 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的再激活 转录酶（TERT）表达作为其TMM，而低级别星形细胞瘤使用替代 端粒延长（ALT）途径。由于它们的基本性质，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。我们的目标是找出新的，磁共振 波谱（MRS）-神经胶质瘤中TERT和ALT的可检测代谢生物标志物， 能够对肿瘤负荷和对治疗的反应进行非侵入性成像。我们的科学前提 先前的研究以及我们的初步数据表明，TERT和ALT是相关的， 具有显著的代谢重编程，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-确定非侵入性1H- 和基于超极化13 C-MRS的TMM状态的成像生物标志物， 目的2-确定1H-和超极化13 C-在神经胶质瘤细胞中的效用 MRS用于体内原位胶质瘤异种移植物中TMM状态的代谢成像;目的3： 通过识别分子机制来机械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。这一建议之所以具有创新性，是因为：1） 虽然TMM与代谢重编程有关，但我们是第一个提出利用TMM的人。 这个链接的非侵入性成像2）我们有机会获得独特的基因工程和病人， 3）我们建议使用无偏的主要模型， 成分分析，以确定TM相关的代谢改变和4）我们有机会， 在应用创新的平移超极化13 C-MRS成像方法方面的专业知识 脑肿瘤这项研究意义重大，因为这里发现的代谢生物标志物 将提供一种非侵入性的手段来成像脑肿瘤的分子特征。 这将使临床医生能够区分肿瘤与正常大脑区域，水肿或坏死 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的肿瘤抑制剂的反应。 TMM抑制剂和对TMM抑制剂耐药性的发展。重要的是，由于 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 除了神经胶质瘤以外的肿瘤类型。

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.