MRI of Early Non-invasive Rodent Mammary Cancers

描述（由申请人提供）：这是一个跨学科提案的第二次修订，专注于早期小鼠乳腺癌的成像和生物学。我们将采用定量连续磁共振成像，伴随组织学，免疫组织化学和x射线荧光显微镜来了解原位乳腺癌的发生和发展的生物学和自然历史。此外，我们将确定MRI参数，以检测乳腺癌的各个阶段，预测未来发展为浸润性癌症的风险，并检测对抗血管生成治疗的反应。我们将研究C3(1)- SV40-Tag（“SVT”）和MMTV-PyMT（“PMT”）转基因小鼠，它们会发展为MIN（乳腺上皮内瘤变，一种类似于人类DCIS的导管内瘤变），并最终发展为浸润性乳腺癌，其组织学进展分别类似于低分化（基础型）和中分化乳腺癌。我们的合作是首次展示高分辨率的非侵入性原位小鼠乳腺癌成像。因此，利用我们在小动物MRI成像和癌症生物学方面的独特优势，我们处于独特的位置，可以进行这些高度整合的研究。我们提出以下具体目标，利用我们的高场小动物MRI扫描仪，阿贡国家实验室的x射线荧光显微镜，以及本-梅癌症研究部门使用动物模型进行的广泛乳腺生物学研究。本研究的具体目的是：1。优化癌前病变和导管内肿瘤改变的功能和解剖MRI。发展准确的MRI与组织学，免疫组织化学和x射线荧光图像的联合登记。2. 以病理评估为金标准，测量MRI检测早期乳腺癌和癌前病变的敏感性和特异性。3. 对SVT和PMT小鼠的乳腺癌自然史进行连续影像学研究。确定MRI检测到的早期病变进展到侵袭期的百分比。识别mri可检测的生理和解剖标记，以区分恶性和良性变化，并预测癌症是否会进展。在每个时间点，一些小鼠将被处死，以便MRI参数可以与组织学，免疫组织化学和x射线荧光图像相关联。4. 使用连续MRI评估SVT小鼠早期癌症对B20（一种结合小鼠VEGF的贝伐单抗型单克隆抗体）的反应。在MR研究的每个时间点，将牺牲几只小鼠，以便MRI结果可以与生物标志物相关联。这项研究为早期乳腺癌的研究开辟了一个新的范式——一种涉及影像学和肿瘤生物学的跨学科方法——使我们能够改善乳腺癌的检测和控制。

DESCRIPTION (provided by applicant): This is a second revision of a transdisciplinary proposal focusing on imaging and biology of early murine mammary cancers. We will employ quantitative serial magnetic resonance imaging with accompanying histology, immunohistochemistry, and X-ray fluorescence microscopy to understand the biology and natural history of in situ mammary cancer at initiation and progression. In addition, we will identify MRI parameters that detect various stages of mammary cancer, predict the future risk of progression to invasive cancer, and detect response to anti-angiogenic therapy. We will study C3(1)- SV40-Tag ('SVT') and MMTV-PyMT ('PMT') transgenic mice that develop MIN (mammary intraepithelial neoplasia; an intraductal neoplasia similar to DCIS in humans) and eventually invasive mammary cancers with a histological progression that is similar to poorly differentiated (basal type) and moderately differentiated breast cancers, respectively. Our collaboration was the first to demonstrate high resolution non-invasive imaging of in situ murine mammary cancer. Therefore, we are uniquely positioned to perform these highly integrated studies that take advantage of our unique strengths in small animal MRI imaging and cancer biology. We propose the following specific aims, taking advantage of our high field small animal MRI scanner, X-ray fluorescence microscopy at the Argonne National Labs, and extensive mammary gland biology research using animal models at the Ben-May Department of Cancer Research. The Specific Aims of the research are: 1. Optimize functional and anatomic MRI of pre-cancerous and intraductal neoplastic changes. Develop accurate co-registration of MRI with histology, immunohistochemistry and X-ray fluorescence images. 2. Measure sensitivity and specificity of MRI for detection of early mammary cancers and pre-cancers using pathologic assessment as the gold standard. 3. Perform a serial imaging study of the natural history of mammary cancer in the SVT and PMT mice. Determine what percentage of early stage lesions detected by MRI progresses to the invasive stage. Identify MRI-detectable physiologic and anatomic markers that differentiate malignant from benign changes, and predict whether cancers will progress. At each time point some mice will be sacrificed so that MRI parameters can be correlated with histology, immunohistochemistry, and X-ray fluorescence images. 4. Use serial MRI to evaluate response of early cancers to B20 (a bevacizumab-type monoclonal antibody that binds mouse VEGF) in the SVT mice. At each time point studied by MR, several mice will be sacrificed so that MRI findings can be correlated with biomarkers. This research develops a new paradigm for the study of early breast cancer - a transdisciplinary approach involving imaging and tumor biology - allowing us to improve breast cancer detection and control.