Quantitative MRSI for the prediction of response to chemoradiation therapy in GBM

描述(由申请人提供)：目前监测多形性胶质母细胞瘤(GBM)进展的标准在很大程度上依赖于使用Macdonald标准(MC)增强的T1加权MRI上肿瘤强化区域的变化。然而，基底膜固有的异质性，以及与手术切除相关的体积和生理变化，使得这一二维评估策略成为问题。此外，在放射治疗中加入替莫唑胺(TMZ)会显著增加假性进展的发生率，进一步使疗效测定复杂化。很明显，在当今分子靶向治疗的时代，细胞毒性可能不是主要的治疗效果，对比剂增强MRI不足以监测反应和进展。人们迫切需要更复杂、更可靠的技术。质子磁共振波谱成像(1H-MRSI)是一种很有前途的技术，它基于组织内分子物种的独特磁性，提供了一种非侵入性的手段来区分肿瘤进展和治疗后的变化。此外，如果1H-MRS生物标记物得到量化和标准化，1H-MRSI可用于监测引起广泛代谢变化的治疗的反应，如组蛋白去乙酰基酶抑制剂Suberoylanilde羟肟酸(SAHA)。因此，这项工作建议实施最先进的1H-MRSI技术，以生成整个大脑的三维代谢物地图，该地图可以与其他成像研究以临床有用的方式共同注册。通过分析埃默里大学以这种方式处理的临床试验的大量数据集，1)将开发用于确定肿瘤体积和细胞内信号密度的分割算法，2)将确定1H-MRS可见代谢物与标准MR图像体积的空间一致性。这些标准化算法随后将被用来产生反应载体，这些反应载体将对照当前使用的反应标准和观察的临床结果进行测试，以评估它们在确定肿瘤对TMZ、放射和SAHA疗法的反应方面的有效性。这项工作的预期结果是使1H-MRSI和相关的生物信息学技术可用于临床，并成为脑瘤患者标准评估的一部分。最后，拟议项目将作为申请者培训的框架 该计划旨在整合基本的分析技术和肿瘤成像技术，以帮助申请者实现职业目标，即成为一名内科科学家，专注于恶性疾病的影像引导治疗计划。

DESCRIPTION (provided by applicant): The current standard for monitoring glioblastoma multiforme (GBM) progression relies heavily on the changes of enhancing tumor regions on contrast-enhanced, T1-weighted MRI using the Macdonald Criteria (MC). However, the inherent heterogeneity of GBM along with the volume and physiological changes associated with surgical resection make this two-dimensional assessment strategy problematic. Moreover, the addition of temozolomide (TMZ) to radiation therapy significantly increases the incidence of pseudo progression, further complicating response determination. It has become apparent that in the present era of molecularly-targeted therapy, when cytotoxicity may not be the primary therapeutic effect, contrast- enhanced MRI is inadequate for monitoring response and progression. More sophisticated and reliable techniques are desperately needed. Proton magnetic resonance spectroscopic imaging (1H-MRSI) is a promising technique that offers a non-invasive means to differentiate tumor progression from post-treatment changes based on the unique magnetic properties of molecular species within tissues. Furthermore, 1H-MRSI can be used to monitor response to therapies that cause widespread metabolic alterations -like suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor -if 1H-MRS biomarkers are quantified and standardized. As such, this work proposes to implement state-of-the-art 1H-MRSI technology to generate three-dimensional metabolite maps of the entire brain that can be co-registered with other imaging studies in a clinically useful fashion. By analyzing numerous data sets from clinical trials at Emory University processed in this fashion, 1) a segmentation algorithm for determining tumor volume and intracellular signal density will be developed, and 2) the spatial coherence of 1H-MRS-visible metabolites with standard MR image volumes will be determined. These standardized algorithms will then be used 3) to produce response vectors that will be tested against currently used response criteria and observed clinical outcomes to evaluate their effectiveness in determining tumor response to TMZ, radiation, and SAHA therapy. The intended outcome of this work is to make 1H-MRSI and the associated bioinformatic techniques practical for clinical use and a part of the standard assessment of brain tumor patients. Lastly, the proposed project will serve as a framework for the applicant's training plan, which is specifically designed to integrate basic analytical techniques and tumor imaging technology to assist the applicant in achieving the career goal of becoming a physician-scientist with a focus in image-guided therapy planning for malignant disease.