Cell invasion, motility, and proliferation level estimate maps in gliomas

描述(申请人提供)：脑肿瘤治疗反应的标准临床评估包括检查标准磁共振成像(MRI)扫描上的对比度增强和T2加权信号异常。虽然这些技术提供了关于肿瘤病理生理学的重要信息，但它们不能直接显示肿瘤的生长和侵袭。过去20年的大量研究表明，肿瘤细胞的侵袭远远超出了传统MRI扫描发现的异常边缘，这种侵袭是导致最常见和最恶性的脑肿瘤--多形性胶质母细胞瘤(GBM)预后不良和100%病死率的主要原因。因此，本项目的总体目标是建立一个有价值的临床影像生物标志物，用于利用弥散磁共振技术对脑肿瘤的生长和侵袭进行可视化和量化。在我们的初步数据中，扩散磁共振成像对肿瘤细胞密度很敏感，扩散磁共振成像随时间的体素变化可以用来预测化疗和抗血管生成治疗的反应。在最近的一篇手稿中，我们开发了一个新的ADC变化的时空模型，旨在量化体素方向的微观增殖和细胞侵袭率，称为细胞侵袭、运动和增殖 水平估计(CIMPLE)地图。我们的初步数据表明，CIMPLE图与恶性潜能的磁共振波谱测量相关，与肿瘤分级相关，可以预测未来增强的区域，预测贝伐单抗治疗复发性胶质母细胞瘤患者的生存，并且在空间上与氨基酸摄取的异常正电子发射断层扫描测量很好地相关。尽管我们实验室的初步结果很有希望，但正如当前提案中的具体实验所概述的那样，还需要进行更多的测试和改进。具体目标#1专注于通过探索高角分辨率扩散成像(HARDI)的使用来改进用于高级CIMPLE地图应用的扩散加权图像采集。这一特定目标的成功将使CIMPLE图能够通过更高的信噪比扩散图像以高精度计算，并创建一种基于张量的CIMPLE图的解决方案，该解决方案可能提供肿瘤侵袭的特定方向图。具体目标#2将重点测试放射治疗期间计算的CIMPLE图是否是标准治疗中肿瘤反应的早期预测生物标志物。具体地说，我们的目标是确定CIMPLE图是否准确预测未来肿瘤进展的空间区域，以及预测6个月和12个月的无进展和总生存期。最后，具体目标#3将侧重于通过使用肿瘤复发的组织学信息和肿瘤增殖的18F-氟-胸腺嘧啶核苷正电子发射断层扫描测量来验证CIMPLE图。这一目标的成功完成将为非侵入性CIMPLE MAP的增殖和侵袭率测量提供更多的证据。 公共卫生相关性：神经肿瘤界普遍认为，目前监测恶性胶质瘤生长和治疗反应的方法是不够的，特别是在试图检测脑瘤侵袭时。本项目旨在进一步建立、验证和临床翻译CIMPLE图谱，作为量化胶质瘤肿瘤细胞侵袭和增殖的非侵入性成像替代物。该项目的成功完成将有助于建立CIMPLE地图，作为个性化的临床监测工具，帮助定制药物选择和检测个别患者的药物失败 比传统技术快得多。

DESCRIPTION (provided by applicant): Standard clinical assessment of brain tumor response to treatment consists of examining contrast enhancement and T2-weighted signal abnormalities on standard magnetic resonance imaging (MRI) scans. While these techniques provide important information regarding tumor pathophysiology, they do not enable direct visualization of tumor growth and invasion. Numerous studies over the past 20 years have shown that tumor cell invasion extends well beyond the margins of abnormalities detected on traditional MRI scans, and this invasion is the primary reason for poor prognosis and 100% fatality rate in glioblastoma multiforme (GBM), the most common and malignant type of brain tumor. Therefore, the overall goal of this project is to establish a valuable clinical imaging biomarker fr visualization and quantification of brain tumor growth and invasion using diffusion MRI techniques. We have demonstrated in our preliminary data that diffusion MRI is sensitive to tumor cell density, and voxel-wise changes in diffusion MRI over time can be used to predict the response to both chemotherapy and anti-angiogenic therapies. In a recent manuscript, we have developed a novel spatiotemporal model of ADC change aimed at quantifying voxel-wise microscopic proliferation and cell invasion rates termed Cell Invasion, Motility, and Proliferation Level Estimate (CIMPLE) maps. Our preliminary data suggests CIMPLE maps correlate with MR spectroscopy measurements of malignant potential, correlate with tumor grade, may predict regions of future contrast enhancement, predict survival in patients with recurrent glioblastoma treated with bevacizumab, and spatially correlates well with abnormal positron emission tomography measurements of amino acid uptake. Despite promising preliminary results from our laboratory, more testing and improvements are necessary as outlined in the specific experiments in the current proposal. Specific Aim #1 focuses on improving the diffusion-weighted image acquisition for advanced CIMPLE map applications by exploring the use of high angular resolution diffusion imaging (HARDI). Success of this specific aim will allow CIMPLE maps to be calculated with high accuracy through higher signal-to-noise diffusion images as well as create a tensor-based solution to CIMPLE maps that may provide directionally-specific maps of tumor invasion. Specific Aim #2 will focus on testing whether CIMPLE maps calculated during radiotherapy are early predictive biomarkers of tumor response to standard therapy. Specifically, we aim to determine whether CIMPLE maps accurately predict spatial regions of future tumor progression as well as predict six- and twelve-month progression-free and overall survival. Lastly, Specific Aim #3 will focus on validating CIMPLE maps through the use of histological information at tumor recurrence and 18F-fluoro-thymidine positron emission tomography measurements of tumor proliferation. Successful completion of this aim will provide additional evidence validating non-invasive CIMPLE map measurements of proliferation and invasion rate. PUBLIC HEALTH RELEVANCE: There is a general consensus in the neuro-oncology community that current methods of monitoring malignant glioma growth and response to treatment are inadequate, particularly when trying to detect brain tumor invasion. This project aims to further establish, validate, and clinically translate CIMPLE maps as a non-invasive imaging surrogate for quantification of tumor cell invasion and proliferation in gliomas. Successful completion of this project will help establish CIMPLE maps as a personalized clinical monitoring tool that will help tailor drug selection and detect drug failure in individual patients much sooner than conventional techniques.