MRI of Early Non-invasive Rodent Mammary Cancers

描述（由申请人提供）：这是一项跨学科提案的第二次修订，重点是早期小鼠乳腺癌的成像和生物学。我们将采用定量序列磁共振成像与伴随的组织学，免疫组织化学和X射线荧光显微镜，以了解原位乳腺癌的生物学和自然史的开始和进展。此外，我们将确定MRI参数，检测乳腺癌的各个阶段，预测未来进展为浸润性癌症的风险，并检测抗血管生成治疗的反应。我们将研究C3（1）-SV 40-Tag（“SVT”）和MMTV-PyMT（“PMT”）转基因小鼠，其分别发展MIN（乳腺上皮内瘤形成;类似于人类DCIS的导管内瘤形成）和最终具有类似于低分化（基底型）和中等分化乳腺癌的组织学进展的浸润性乳腺癌。我们的合作是第一次展示原位小鼠乳腺癌的高分辨率非侵入性成像。因此，我们处于独特的地位，可以利用我们在小动物MRI成像和癌症生物学方面的独特优势进行这些高度综合的研究。我们提出了以下具体目标，利用我们的高场小动物MRI扫描仪，X射线荧光显微镜在阿贡国家实验室，和广泛的乳腺生物学研究使用动物模型在本-梅癌症研究部。本研究的具体目的是：1.优化癌前病变和导管内肿瘤变化的功能和解剖MRI。开发MRI与组织学、免疫组织化学和X射线荧光图像的准确配准。 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灵敏度和特异性。 3.在SVT和PMT小鼠中进行乳腺癌自然史的系列成像研究。确定MRI检测到的早期病变进展到侵袭性阶段的百分比。识别MRI可检测的生理和解剖标志物，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，将处死一些小鼠，使得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.使用系列MRI评价SVT小鼠中早期癌症对B20（一种结合小鼠VEGF的贝伐珠单抗型单克隆抗体）的反应。在MR研究的每个时间点，将处死几只小鼠，以便MRI结果与生物标志物相关。 这项研究为早期乳腺癌的研究开发了一种新的范式-一种涉及成像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。 公共卫生相关性：我们建议使用啮齿动物乳腺/体内/的高分辨率功能和解剖磁共振成像，以提高对浸润前人类乳腺癌及其前体的自然史的理解，以评估针对早期癌症的治疗，并确定早期癌症和癌症风险的MRI标记物。这项研究将改善高危病变和早期乳腺癌的临床管理。我们将研究小鼠乳腺上皮内瘤变（MIN）;这种早期非侵袭性瘤变与人类导管原位癌（DCIS）非常相似。

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. PUBLIC HEALTH RELEVANCE: We propose to use high-resolution functional and anatomic magnetic resonance imaging of rodent mammary glands /in vivo/ to improve understanding of the natural history of pre-invasive human breast cancer and its precursors, to evaluate therapies that target early cancers, and to identify MRI markers for early cancers and cancer risk. This research will lead to improvements in the clinical management of high risk lesions and early breast cancer. We will study mouse mammary intra-epithelial neoplasia (MIN); this early, non-invasive neoplasia is very similar to ductal carcinoma in situ, or DCIS, in humans.