Comprehensive Evaluation of OGSE DWI for Assessing Tumor Treatment Response

描述(由申请人提供)：这项提案是作为我们的申请2R01 CA109106的配套拨款提交的，该申请于2011年6月由BMIT-B研究科审查，并被授予12(第二个百分位数)的优先分数，没有建议削减预算。我们的总体目标是继续开发、评估和验证一种新的磁共振成像(MRI)技术，该技术是治疗前后肿瘤状态的敏感指标，并提供关于组织微结构的独特信息。随后，与研究科的建议相比，Grant CA109106获得了62%的预算削减。因此，用这笔赠款开展的工作已被修订，并大大缩小了范围，它将不再支持拟议和批准的大多数动物研究或治疗效果比较。这项建议的目的是为那些已获批准但未获资助的研究争取补充支持，我们(和研究科)认为这些研究是我们评估这一新方法的一部分。先前的研究已经令人信服地表明，弥散加权磁共振(DW-MRI)可以报告肿瘤在生长和后续治疗期间的变化。然而，只有在细胞密度充分改变的关键时间过去之后，可检测到的变化才会发生，而传统的DW-MRI对细胞内更早或更细微的变化不敏感。我们开发了一种替代技术，振荡梯度自旋回波(OGSE)DW-MRI，它对限制组织水自由扩散的微结构特征非常敏感，这些特征比细胞小得多。OGSE测量可以选择性地对不同大小的特征敏感，它们似乎能够在细胞密度发生变化之前检测到细胞内的变化，并且它们提供了一种新型的光谱数据，可以进行分析以获得定量的结构信息。我们已经证明，OGSE成像显示了肿瘤内更大的异质性，在更高的对比度下，它对细胞内的特征如核大小敏感，而且它似乎对治疗后肿瘤的早期变化更敏感。我们建议应用优化的OGSE方法来测量随着肿瘤的生长而发生的变化，以及对三种不同类别的靶向治疗的响应，在体内的小鼠模型中。我们将建立早期OGSE方法如何检测肿瘤对治疗的反应，这些变化预测未来结果的良好程度，以及哪些OGSE参数与细胞密度、细胞凋亡和增殖的变化相关。OGSE数据将与同一肿瘤的共同注册的定量组织学和免疫组织化学切片相关联，以验证测量结果的解释。我们还将通过对适当复杂的隔间系统中的水进行详细的计算机模拟，进一步协助解释OGSE数据。我们的总体目标是验证OGSE方法作为肿瘤临床前研究的实验工具。

DESCRIPTION (provided by applicant): This proposal is being submitted as a companion grant to our application 2R01 CA109106 which was reviewed by the BMIT-B Study Section in June 2011 and awarded a priority score of 12 (2nd percentile) with no recommended budget cuts. Our overall aims are to continue the development, evaluation and validation of a novel magnetic resonance imaging (MRI) technique that is a sensitive indicator of tumor status, before and after treatment, and which provides unique information non-invasively on tissue microstructure. Grant CA109106 was subsequently awarded with a 62% budget reduction compared to what the Study Section recommended. The work being performed with that grant has therefore been amended and substantially reduced in scope, and it no longer will support most of the animal studies or comparisons of treatment effects that were proposed and approved. This proposal aims to secure supplementary support for those studies that were approved but not funded, and which we (and the Study Section) consider essential as part of our evaluation of this new methodology. Previous studies have convincingly shown that diffusion weighted MRI (DW-MRI) can report on changes in tumors during growth and following treatment. However, detectable changes occur only after a critical time has elapsed, when cell density has altered sufficiently, and conventional DW-MRI is not sensitive to earlier or more subtle changes within cells. We have developed an alternative technique, oscillating gradient spin-echo (OGSE) DW-MRI, which is uniquely sensitive to microstructural features much smaller than a cell which restrict the free diffusion of tissue water. OGSE measurements may be sensitized selectively to features of different sizes, they appear to be able to detect changes within cells before there are changes in cell density, and they provide a new type of spectral data which can be analyzed to obtain quantitative structural information. We have shown that OGSE imaging reveals greater heterogeneity within tumors, and at higher contrast, that it is sensitive to intra-cellular features such as nuclear size, and that it seems more sensitive to earlier changes in tumors following treatment. We propose to apply optimized OGSE methods to measure changes that occur with the growth of tumors, and in response to three different classes of targeted treatments, in mouse models in vivo. We will establish how early OGSE methods can detect the response of tumors to treatments, how well these changes predict later outcomes, and which OGSE parameters correlate with changes in cellularity, apoptosis and proliferation. The OGSE data will be correlated with co-registered quantitative histological and immunohistochemical sections of the same tumor to verify the interpretation of the measurements. We will also further assist the interpretation of OGSE data by performing elaborate computer simulations of water in compartmental systems of appropriate complexity. Our overall aim is to validate OGSE methods as an experimental tool for pre-clinical studies of tumors.