Temporospatial changes of TSPO expression in glioblastoma in response to therapy and during disease progression – a multimodal TSPO PET, amino acid PET, and MRI study

胶质母细胞瘤中 TSPO 表达在治疗反应和疾病进展过程中的时空变化——多模式 TSPO PET、氨基酸 PET 和 MRI 研究

• 批准号: 512125201
• 负责人: Professorin Dr. Nathalie Albert
• 金额: --
• 依托单位: Klinik und Poliklinik für Nuklearmedizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/512125201?language=en
• 关键词: Temporospatial; changes; TSPO; expression; glioblastoma

Our previous work and that of others has shown that TSPO PET and FET PET demonstrate diverging uptake patterns in malignant glioma and provide complementary information to contrast enhanced MRI. Increased TSPO PET signal correlates with tumor grade and poor prognosis and, especially in the relative absence of FET enhancement, may reflect therapy induced changes in the tumor and its inflammatory microenvironment. However, longitudinal assessment of TSPO signaling in response to therapy and during disease progression and its impact on the clinical outcome and individual prognosis of glioblastoma patients has not been assessed so far. Therefore, this project aims to visualize temporal and spatial changes of TSPO expression by means of a single arm observational study using longitudinal multimodal TSPO / FET PET and ceMRI for patients with glioblastoma, and to correlate imaging findings with changes on the cellular and molecular level as well with the clinical outcome. In work package 1 patients with newly diagnosed brain tumors suspicious for glioblastoma (n=58) will be recruited and prospectively enrolled. Recruitment phase of the study will be 18 months with follow-up of another 18 months. All data retrieved from clinical workup, clinical-follow-up, imaging and neuropathological analysis will be put into an electronic database. Tumor specimen collected during tumor resection and serial stereotactic biopsies will be performed using an image guided neuronavigation system. Localizations of tissue samples will be assigned to PET and MRI data, which enables a precise spatial correlation of PET information with histopathological findings and pathway analyses for project A2/3. This collaboration with project A2/A3 allows in-depth analyses of changes of the tumor microenvironment, cellular contributions to the TSPO signal (myeloid cells vs. tumor cells) and molecular alterations in a unique longitudinal study cohort with tissue samples obtained with TSPO PET image guidance at primary diagnosis and at relapse. Work package 2 focusses on advanced image analysis of the multimodal imaging data and its correlation with clinical and neuropathological data obtained in work package 1. The analyses include pharmacokinetic modelling, machine learning and deep learning approaches to perform non-invasive tissue classification, distinguish therapy responders from non-responders at an early time point and to predict the time and localization of tumor recurrence and ultimately, to link imaging features with overall survival.

我们以前的工作和其他人的工作已经表明，TSPO PET和FET PET表现出不同的恶性胶质瘤的摄取模式，并提供互补的信息，对比增强MRI。增加的TSPO PET信号与肿瘤分级和不良预后相关，尤其是在相对缺乏FET增强的情况下，可能反映了肿瘤及其炎症微环境的治疗诱导的变化。然而，迄今为止尚未评估TSPO信号传导对治疗的响应和疾病进展期间的纵向评估及其对胶质母细胞瘤患者的临床结果和个体预后的影响。 因此，本项目旨在通过对胶质母细胞瘤患者进行纵向多模式TSPO / FET PET和ceMRI的单臂观察性研究，可视化TSPO表达的时间和空间变化，并将成像结果与细胞和分子水平的变化以及临床结果相关联。 在工作包1中，将招募并前瞻性入组疑似胶质母细胞瘤的新诊断脑肿瘤患者（n=58）。研究的招募期为18个月，随访期为另外18个月。从临床检查、临床随访、成像和神经病理学分析中检索到的所有数据将输入电子数据库。将使用图像引导神经导航系统进行肿瘤切除术和连续立体定向活检期间采集的肿瘤标本。组织样本的定位将分配给PET和MRI数据，这使得PET信息与项目A2/3的组织病理学发现和路径分析具有精确的空间相关性。与项目A2/A3的合作允许在一个独特的纵向研究队列中深入分析肿瘤微环境的变化、细胞对TSPO信号的贡献（骨髓细胞与肿瘤细胞）和分子改变，该队列使用在初步诊断和复发时通过TSPO PET图像引导获得的组织样本。工作包2侧重于多模态成像数据的高级图像分析及其与工作包1中获得的临床和神经病理学数据的相关性。这些分析包括药代动力学建模、机器学习和深度学习方法，以进行非侵入性组织分类，在早期时间点区分治疗应答者和无应答者，并预测肿瘤复发的时间和位置，最终将成像特征与总生存期联系起来。