Noninvasive assessment of tumor malignancy

描述(申请人提供)：有效治疗人脑肿瘤是一个重大挑战。潜在的问题之一是缺乏可靠的、非侵入性的手段来评估肿瘤的恶性程度和评估治疗反应。目前的建议旨在开发和评估一种新的、非侵入性的评估肿瘤活动性的方法，该方法基于磁共振血管成像(MRA)确定的血管形状的定量统计测量。虽然我们同时在人类受试者身上研究这种方法，但由于无法获得全脑组织学信息，许多问题在人类患者身上不能轻易解决。这项建议采用了两种基因工程小鼠模型，在这些模型中，肿瘤在适当的解剖位置、适当的组织学和可预测的时间进程中可靠地产生CTE。一种模型是胶质瘤，从无瘤发展到低级别胶质瘤，再到3级胶质瘤，再到胶质母细胞瘤。第二个模型是脉络丛癌，大量血管丰富，通过产生微小的恶性肿瘤灶来模拟转移性肿瘤的生长，然后生长到较大的体积。本提案旨在开发和测试拟议的肿瘤活动性评估方法，以便：a)确定新方法是否可以正确地对不断变化的肿瘤分级进行分类，并在抗血管生成和更通用的治疗下预测肿瘤的治疗反应；b)比较新方法与更传统的成像评估技术的能力，包括测量肿瘤体积、灌注成像和渗透性成像；以及c)确定MRA所感知的血管形态异常是否可以与组织学评估的癌症诱导的血管壁变化相关联。这项提议解决了一个主要的临床问题，这个问题一直很难通过传统方法解决。同时，这项拟议的工作还解决了重要的生物学问题，这些问题可能会导致对肿瘤生长机制的深入了解。这项拟议工作的长期潜力不仅包括改进肿瘤治疗的早期临床评估手段，还包括在临床前动物模型和人类受试者中开发和测试治疗药物的新方法。

DESCRIPTION (provided by applicant): Effective treatment of human brain tumors poses a major challenge. One of the underlying problems is lack of reliable, noninvasive means of assessing tumor malignancy and of assessing treatment response. The current proposal aims to develop and evaluate a new, noninvasive method of assessing tumor activity based upon quantitative, statistical measures of vessel shape determined from magnetic resonance angiograms (MRA). Although we are simultaneously pursuing this approach in human subjects, there are many issues that cannot be readily addressed in human patients since whole-brain histological information is not available. This proposal employs two genetically engineered mouse models in which tumors reliably arise cte novo, in the appropriate anatomical location, with appropriate histology, and with a predictable time course. One model is a glioma that progresses from no tumor to low-grade glioma to grade 3 glioma to glioblastoma. The second model is a heavily vascular choroid plexus carcinoma that mimics the growth of metastatic tumors by producing microscopic foci of malignancy that subsequently grow to large size. This proposal aims to develop and test the proposed method of tumor activity assessment so as: a) to determine whether the new approach can both correctly classify changing tumor grade and predict tumor treatment response under both anti-angiogenic and more generic therapy, b) to compare the ability of the new method to that of more traditional imaging assessment techniques including measurement of tumor volume, perfusion imaging, and permeability imaging, and c) to determine if vessel shape abnormalities as perceived by MRA can be correlated with cancer-induced changes to the vessel wall as evaluated by histology. This proposal addresses a major clinical problem that has been highly refractory to solution by traditional methods. At the same time, the proposed work also addresses important biological questions that could lead to insights into mechanisms of tumor growth. The long term potential of the proposed work includes not only improved means of early clinical evaluation of tumor treatment, but also new methods of developing and testing therapeutic agents in both preclinical animal models and human subjects.