Noninvasive assessment of tumor malignancy

描述（由申请人提供）：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，非侵入性的方法来评估肿瘤活动的基础上，定量，统计测量血管形状确定从磁共振血管造影（MRA）。虽然我们同时在人类受试者中采用这种方法，但由于无法获得全脑组织学信息，因此在人类患者中存在许多问题。该提案采用了两种基因工程小鼠模型，其中肿瘤可靠地在适当的解剖位置、适当的组织学结构和可预测的时间过程中从头出现。一种模型是从无肿瘤进展到低级别胶质瘤到3级胶质瘤到胶质母细胞瘤的胶质瘤。第二个模型是一个严重的血管脉络丛癌，模拟转移性肿瘤的生长，产生恶性肿瘤的微观病灶，随后生长到大尺寸。本提案旨在开发和测试所提出的肿瘤活性评估方法，以便：a）确定新方法是否能够正确地分类变化的肿瘤等级并预测在抗血管生成和更一般的治疗下的肿瘤治疗反应，B）将新方法的能力与更传统的成像评估技术的能力进行比较，包括测量肿瘤体积，灌注成像，和渗透性成像，以及c）确定由MRA感知的血管形状异常是否可以与由组织学评估的血管壁的癌症诱导的变化相关。该提案解决了传统方法高度难以解决的主要临床问题。与此同时，拟议的工作还解决了重要的生物学问题，这些问题可能导致对肿瘤生长机制的深入了解。这项工作的长期潜力不仅包括改进肿瘤治疗的早期临床评估方法，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.