Validating a mouse model of ovarian cancer for early detection through imaging

 描述（由申请人提供）： 尽管治疗策略取得了进展，但卵巢癌仍然是最致命的妇科恶性肿瘤，也是女性第五大癌症杀手。卵巢癌位于身体深处，早期症状很少，也没有有效的筛查技术，它仍然难以理解，更不用说有效地对抗了。卵巢癌几乎总是在晚期被发现。因此，卵巢癌高风险的女性通常被建议进行预防性卵巢切除术，这可以降低癌症死亡的风险，但伴随着相关的发病率，并可能缩短寿命。 降低卵巢癌死亡率的关键是发展有效的早期检测技术。研究人员已经证明，高分辨率光学成像，包括光学相干断层扫描（OCT）荧光成像（FI）和多光子显微镜（MPM）可以区分人类和小鼠模型中的正常和晚期癌症。然而，早期癌症的成像生物标志物尚不清楚。开发成像标记物在女性中是非常不切实际的，因为检测到的早期癌症数量很少，并且无法随着时间的推移跟踪癌症的发展。需要一种相关的、经验证的早期高级别浆液性癌（HGSC）小鼠模型来开发可转化为女性早期检测系统的成像生物标志物。 具体目标1：建立早期卵巢癌的动物模型。MISIIR-TAg小鼠产生自发性双侧HGSC。因为大多数卵巢癌患者都是绝经后的，我们将通过给予4-乙烯基环己烯二环氧化物（VCD）来增强这种转基因模型，这会诱导选择性卵泡闭锁并模拟绝经。在癌症发展的非常早期的时间点，我们将检查卵巢/输卵管形态，基因表达和细胞表面标志物表达，创建早期OC期间发生的变化的路线图。我们将通过与已发表的基因图谱和策划的数据集进行比较，并验证小鼠和人类组织微阵列中的选定细胞表面标志物，将我们在基因表达方面的发现与女性中的发现进行比较。 具体目标2。开发早期卵巢癌的成像生物标志物。使用经验证的小鼠模型，我们将获得体内光学图像，并开发卵巢和输卵管的定性和定量光学图像特征，以在最早的时间点识别癌症。我们将随着时间的推移跟踪小鼠，并测试这些体内图像标记物对单一和多种模式的灵敏度和特异性，以确定可以可靠检测到癌症的最早时间点。此外，我们将开发针对过表达细胞表面标志物的造影剂，以提高灵敏度。 在该项目结束时，我们将获得必要的信息来开发一种可行的光学成像方法，用于早期检测HGSC，这有可能大大降低这种疾病的死亡率。

 DESCRIPTION (provided by applicant): Despite advances in treatment strategies, ovarian cancer remains the deadliest gynecological malignancy and the 5th largest cancer killer in women. Located deep in the body, with few early symptoms and no effective screening technique, ovarian cancer has remained stubbornly difficult to understand, much less effectively combat. Ovarian cancer is almost always discovered at an advanced stage. Therefore, women at high risk for ovarian cancer are usually counseled to have a prophylactic oophorectomy, which can reduce risk of death from cancer but comes with associated morbidity and may reduce life span. The key to reducing the mortality from ovarian cancer is to develop an effective early detection technique. The investigators have shown that high resolution optical imaging, including optical coherence tomography (OCT) fluorescence imaging (FI), and multiphoton microscopy (MPM) can differentiate normal from advanced stage cancer in humans and mouse models. However, imaging biomarkers of early stage cancer are not yet known. Developing imaging markers is highly impractical in women due to the low number of early stage cancers detected, and the inability to follow cancer development over time. A relevant, validated mouse model of early stage high grade serous carcinoma (HGSC) is needed to develop imaging biomarkers that could be translated to an early detection system for women. Specific Aim 1: Validate a model for early stage ovarian cancer. The MISIIR-TAg mouse develops spontaneous bilateral HGSC. Because most women who develop ovarian cancer are post-menopausal, we will augment this transgenic model with administration of 4-vinylcyclohexene diepoxide (VCD), which induces selective follicular atresia and mimics menopause. At very early time points in cancer development, we will examine ovarian/fallopian tube morphology, gene expression, and cell surface marker expression, creating a roadmap of changes that occur during early OC. We will compare our findings on gene expression to those seen in women by comparison to published gene atlases and curated data sets, as well as validating select cell surface markers in mouse and human tissue microarrays. Specific Aim 2. Develop imaging biomarkers of early stage ovarian cancer. Using the validated mouse model, we will obtain in vivo optical images and develop qualitative and quantitative optical image features of ovaries and fallopian tubes that identify cancer at the earliest time points. We will follow mice over time, and test sensitivity and specificity of these in vivo image markers for single and multiple modalities to determine the earliest time point that cancer can reliably be detected. Additionally, we will develop contrast agents targeted to overexpressed cell surface markers, for potential increase in sensitivity. At the end of this project, we will have the information necessary to develop a viable optical imaging method for early detection of HGSC, which has the potential to dramatically reduce mortality from this disease.