DCE MRI Study for Breast Cancer.

描述（由申请人提供）：尽管最近开发了各种治疗方法，但乳腺癌仍然是女性癌症死亡的第二大原因，也是45至55岁女性死亡的主要原因。抗血管生成治疗方法已被用作治疗癌症的重要手段。然而，针对个体患者的这种抗血管生成疗法的优化仍未解决。抗血管生成剂被认为暂时使异常的脉管系统正常化，并且矛盾地增加血流量并因此增加药物递送至肿瘤。相当大比例的患者对这种抗血管生成疗法没有反应，但尚不清楚失败是由于抗血管生成疗法未能使血管系统正常化还是细胞毒性疗法未能杀死细胞。因此，有必要评估血流量和细胞死亡，以阐明机制，并监测联合治疗的疗效。在本提案中，我们将研究单个MRI采集和分析，以评估两者。动态对比增强（DCE）- MRI已成为评估肿瘤微循环环境的有力工具。在这个建议中，我们介绍了一种新的分析方法DCE-MRI结合绝热近似的组织均匀性模型与水交换模型（ATH-WX）。该分析提供了灌注参数（流量、血管体积分数和血管渗透性-表面积乘积）和细胞结构参数（间质体积分数和细胞内水寿命）的估计值。研究的第一阶段包括一系列实验，以测量ATH-WX模型参数与肿瘤生长期间其他MRI和病理学测量的关联。在第二阶段，我们将测试所提出的用于检测早期治疗反应的ATH-WX模型，并将其测量结果与病理学进行比较，以确定与治疗引起的病理变化最相关的ATH-WX参数。在第三阶段，我们计划应用ATH-WX模型来测量节拍化疗（MCT）的抗血管生成作用，其中使用常规细胞毒性药物来诱导抗血管生成和细胞毒性作用。总之，本研究中收集的临床前实验数据将用于检验我们的主要假设，即所提出的新方法（DCE-MRI与ATH-WX）可以同时提供抗血管生成和细胞毒性反应的定量测量。该项目的结论将提供一种经过全面测试的非侵入性MRI方法，用于定量测量肿瘤微环境。本申请中的拟议实验将为利用这种新的DCE-MRI方法通过及时改变无效的治疗方案来改善患者管理奠定重要的基础。由于MRI是现代医学中普遍使用的无创性方法，因此在临床前环境中开发的方法可以很容易地转化为有效管理肿瘤治疗策略的临床工具。 公共卫生相关性：使用抗血管生成靶向药物或具有节拍时间表的细胞毒性药物评估抗血管生成治疗，需要测量治疗的抗血管生成和细胞毒性作用的有效非侵入性方法。我们的基本假设是，使用组织均匀性与水交换（ATH-WX）模型的绝热近似的单次动态收缩增强MRI测量提供了一种评估抗血管生成治疗的抗血管生成和细胞毒性反应的方法。该提案中的研究将建立一种评估化疗的创新方法，该方法将显着改善包括乳腺癌在内的各种癌症的药物发现和患者管理。

DESCRIPTION (provided by applicant): Breast cancer remains the second leading cause of cancer death in women and the primary cause of death in women ages 45 to 55, despite recent development of various therapies. Anti-angiogenic treatment approaches have been used as important means of treating cancer. However, optimization of such anti-angiogenic therapies for individual patients remains unresolved. Anti-angiogenics are thought to temporarily normalize abnormal vasculature and paradoxically increase blood flow and hence drug delivery to tumors. A substantial proportion of patients do not respond to this anti-angiogenic therapy but it is unclear whether the failure is due to failure of the anti-angiogenic to normalize the vasculature or failure of the cytotoxic to kill cells. It is therefore necessary to assess both blood flow and cell death to elucidate the mechanism and to monitor the efficacy of combined treatments. In this proposal we will investigate a single MRI acquisition and analysis that will allow assessment of both. Dynamic contrast enhanced (DCE) - MRI has emerged as a powerful tool for assessing tumor microcirculation environment. In this proposal we introduce a novel analysis method for DCE-MRI that combines the adiabatic approximation of tissue homogeneity model with a water exchange model (ATH-WX). This analysis provides estimates of both perfusion parameters (flow, vascular volume fraction, and vascular permeability-surface area product) and cell structural parameters (interstitial volume fraction, and intracellular water life time). The first stage of the study is comprised of a series of experiments to measure the association of the ATH-WX model parameters with other MRI and pathology measures during tumor growth. In the second stage, we will test out the proposed ATH-WX model for detection of early treatment response and compare its measures with pathology, in order to determine the ATH-WX parameters that best correlate with pathological changes induced by the therapy. In the third stage, we plan to apply the ATH-WX model to measure the anti-angiogenic effects of metronomic chemotherapy (MCT) in which a conventional cytotoxic drug is used to induce both anti-angiogenic and cytotoxic effects. In overall, the preclinical experimental data collected in this study will be used to test our main hypothesis that the proposed novel method (DCE-MRI with ATH-WX) can provide quantitative measures of both anti-angiogenic and cytotoxic responses simultaneously. The conclusion of this project will deliver a thoroughly tested noninvasive MRI method for quantitative measurement of tumor microenvironment. The proposed experiments in this application will lay important stepping stones toward utilizing this novel DCE-MRI method to improve patient management by allowing timely changes to ineffective treatment regimens. Since MRI is a ubiquitous and noninvasive method commonly used in modern medicine, the developed method in preclinical environment can be easily translated into a clinical tool for effective management of tumor treatment strategies. PUBLIC HEALTH RELEVANCE: Assessment of anti-angiogenic therapy, using either an anti-angiogenic targeted drug or a cytotoxic drug with metronomic schedule, requires an effective non-invasive method of measuring both the anti-angiogenic and cytotoxic effects of the therapies. Our underlying hypothesis is that a single dynamic contract enhanced MRI measurement using the adiabatic approximation of tissue homogeneity with water exchange (ATH-WX) model provides a means of assessing both anti-angiogenic and cytotoxic responses to anti-angiogenic therapies. The research in this proposal will establish an innovative method of assessing chemotherapy that will significantly improve drug discovery and patient management in a variety of cancers including breast cancer.