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，该提案侧重于早期小鼠乳腺癌的成像和生物学。我们将使用定量序列磁共振成像，并伴随着组织学、免疫组织化学和X射线荧光显微镜来了解原位乳腺癌发生和发展的生物学和自然历史。此外，我们将确定检测乳腺癌不同阶段的MRI参数，预测未来进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，它们分别发展为MIN(乳腺上皮内瘤变；一种类似于人类DCIS的导管内瘤变)和最终的浸润性乳腺癌，其组织学进展类似于低分化(基底型)和中分化乳腺癌。我们的合作是第一个展示高分辨率非侵入性成像的原位小鼠乳腺癌。因此，我们在进行这些高度集成的研究方面具有得天独厚的优势，这些研究利用了我们在小动物磁共振成像和癌症生物学方面的独特优势。我们提出了以下具体目标，利用我们的高场小动物核磁共振扫描仪，阿贡国家实验室的X射线荧光显微镜，以及本-梅癌症研究部使用动物模型进行的广泛的乳腺生物学研究。本研究的具体目的是：1.优化癌前病变和导管内肿瘤病变的功能和解剖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联合配准。2.以病理评估为金标准，评价MRI诊断早期乳腺癌及癌前病变的敏感性和特异性。3.对SVT和PMT小鼠乳腺癌的自然病程进行了一系列的影像研究。确定MRI检测到的早期病变进展到侵袭期的百分比。确定MRI可检测的生理和解剖标记物，以区分良恶性病变，并预测癌症是否会进展。在每个时间点，将处死一些小鼠，以便将MRI参数与组织学、免疫组织化学和X射线荧光图像相关联。4.应用系列磁共振成像技术评价SVT小鼠早期肿瘤对B20(一种结合小鼠血管内皮细胞生长因子的贝伐单抗)的反应。在MR研究的每个时间点，将牺牲几只小鼠，以便将MRI结果与生物标记物相关联。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--使我们能够改进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的高分辨率功能和解剖磁共振成像/活体/来提高对侵袭前人类乳腺癌及其前驱疾病的自然历史的了解，评估针对早期癌症的治疗方法，并确定早期癌症和癌症风险的MRI标志物。这项研究将改进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)；这种早期的、非侵袭性的肿瘤与人类的导管原位癌(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.