Comprehensive Evaluation of OGSE DWI for Assessing Tumor Treatment Response

描述（由申请人提供）：该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研究部门审查，并获得了12（第二百分位）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，评估和验证一种新型磁共振成像（MRI）技术，该技术是肿瘤状态的敏感指标，治疗前后，并提供独特的非侵入性组织微观结构信息。补助金CA109106随后被授予，与研究科建议的预算相比，预算减少了62%。因此，这笔拨款正在进行的工作已经进行了修改，并大大缩小了范围，它将不再支持大多数已提出和批准的治疗效果的动物研究或比较。本提案旨在为那些已获批准但未获资助的研究提供补充支持，我们（和研究组）认为这些研究是我们评估新方法的重要组成部分。先前的研究令人信服地表明，扩散加权MRI （DW-MRI）可以报告肿瘤在生长过程中和治疗后的变化。然而，检测到的变化只有在细胞密度发生充分变化的关键时间过去后才会发生，而传统的DW-MRI对细胞内早期或更细微的变化不敏感。我们已经开发了一种替代技术，振荡梯度自旋回波（OGSE） DW-MRI，它对比限制组织水自由扩散的细胞小得多的微结构特征具有独特的敏感性。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变化之前检测到细胞内部的变化，并且它们提供了一种新型的光谱数据，可以通过分析获得定量的结构信息。我们已经表明，OGSE成像揭示了肿瘤内部更大的异质性，并且在更高的对比度下，它对细胞内特征（如核大小）敏感，并且似乎对治疗后肿瘤的早期变化更敏感。我们建议在体内小鼠模型中应用优化的OGSE方法来测量随着肿瘤生长而发生的变化，以及对三种不同类型的靶向治疗的反应。我们将确定早期OGSE方法如何检测肿瘤对治疗的反应，这些变化如何预测后期结果，以及哪些OGSE参数与细胞结构、凋亡和增殖的变化相关。OGSE数据将与同一肿瘤的共同登记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。我们还将通过在适当复杂性的隔室系统中进行精细的水计算机模拟，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.