Noninvasive assessment of tumor malignancy

描述（由申请人提供）：有效治疗人类脑肿瘤是一项重大挑战。其中一个潜在的问题是缺乏可靠的，无创的手段来评估肿瘤的恶性程度和评估治疗反应。目前的提案旨在开发和评估一种新的、无创的评估肿瘤活性的方法，该方法基于定量的、由磁共振血管造影（MRA）确定的血管形状的统计测量。虽然我们同时在人类受试者中追求这种方法，但由于无法获得全脑组织学信息，因此在人类患者中有许多问题无法轻易解决。该建议采用两种基因工程小鼠模型，其中肿瘤可靠地从头出现，在适当的解剖位置，具有适当的组织学，并具有可预测的时间过程。一种模型是胶质瘤从无肿瘤发展到低级别胶质瘤到3级胶质瘤再到胶质母细胞瘤。第二种模型是血管密集的脉络膜丛癌，通过产生恶性肿瘤的显微灶，随后生长到较大的尺寸，模拟转移性肿瘤的生长。本提案旨在开发和测试所提出的肿瘤活动性评估方法，以便：A)确定新方法是否能够在抗血管生成和更通用的治疗方法下正确分类变化的肿瘤分级和预测肿瘤治疗反应；b)将新方法的能力与更传统的影像学评估技术（包括肿瘤体积测量、灌注成像和通透性成像）进行比较；c)确定MRA感知到的血管形状异常是否与组织学评估的癌症诱导的血管壁变化相关。这一建议解决了一个主要的临床问题，一直高度难以解决的传统方法。同时，提出的工作也解决了重要的生物学问题，可能导致深入了解肿瘤生长机制。这项工作的长期潜力不仅包括改善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剂的新方法。

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.