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）进展的标准严重依赖于使用Macdonald标准（MC）的对比增强T1加权MRI上增强肿瘤区域的变化。然而，GBM的固有异质性沿着与手术切除相关的体积和生理变化使得这种二维评估策略存在问题。此外，在放射治疗中加入替莫唑胺（TMZ）显著增加了假性进展的发生率，使反应确定进一步复杂化。很明显，在目前的分子靶向治疗时代，当细胞毒性可能不是主要的治疗效果时，对比增强MRI不足以监测反应和进展。迫切需要更复杂和可靠的技术。质子磁共振波谱成像（1H-MRSI）是一种很有前途的技术，它提供了一种非侵入性的手段，根据组织内分子种类的独特磁性，区分肿瘤进展和治疗后的变化。此外，如果1H-MRS生物标志物被定量和标准化，1H-MRSI可用于监测对引起广泛代谢改变的治疗的反应-如辛二酰苯胺异羟肟酸（SAHA），一种组蛋白去乙酰化酶抑制剂。因此，这项工作提出了实施最先进的1H-MRSI技术，以生成整个大脑的三维代谢物图，可以以临床有用的方式与其他成像研究共同注册。通过分析以这种方式处理的来自埃默里大学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，以及2）将确定1H-MRS可见代谢物与标准MR图像体积的空间相干性。然后将使用这些标准化算法3）产生响应向量，将根据当前使用的响应标准和观察到的临床结果进行测试，以评估其在确定肿瘤对TMZ、放射和SAHA治疗的响应方面的有效性。这项工作的预期成果是使1H-MRSI和相关的生物信息学技术实用于临床使用，并成为脑肿瘤患者标准评估的一部分。最后，拟议项目将作为申请人培训的框架 计划，这是专门设计的，以整合基本的分析技术和肿瘤成像技术，以帮助申请人在实现成为一个医生，科学家的职业目标，重点在恶性疾病的图像引导治疗规划。

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.