Developing non-human primate models for ovarian cancer

摘要 上皮性卵巢癌是一种致命的疾病，没有有效的治疗方法。癌症通常在 已经对治疗无效的晚期患者。因此，迫切需要界定 研究这种癌症的生物学，并开发早期诊断和治疗的新方法。转基因 移植了肿瘤细胞系的小鼠或啮齿动物是唯一可用于研究卵巢癌的哺乳动物模型。 小鼠不会自发地患上卵巢癌或其前驱病变。相当大比例的高品级 浆液性卵巢癌是由转化的分泌性输卵管上皮细胞移植到卵巢上的。 卵巢的外表面。在小鼠中，卵巢被包裹在法氏囊中，因此不能真正 模拟人卵巢表面的肿瘤植入。卵巢癌的其他主要亚型， 透明细胞癌和子宫内膜样癌起源于子宫内膜异位病变。子宫内膜异位症不是一种 自发地发生在老鼠身上。这些差异表明需要一种更高阶的动物模型。 这更能代表人类的解剖学和生理学。更可取的将是一种模式，在这种模式中 卵巢肿瘤或至少其前驱病变是自发发生的。在这项拨款申请中，我们建议 恒河猴可以发展成更好地模拟卵巢的三个主要亚群的模型 癌症。恒河猴的解剖和内分泌生理学与女性高度相似，而子宫内膜异位症是一种 自发发生的状态。我们已经确定了恒河猴的卵巢和腹膜肿瘤 子宫内膜异位症提示这些肿瘤可能是自发发生的透明细胞或 子宫内膜样癌。因此，这项建议的目标是将恒河猴发展为 卵巢癌的主要亚型。在目标1中，我们将进行从近端到 对恒河猴输卵管远端进行检查，以确定高级别浆液性肿瘤的前驱病变。在目标2中，我们 将显示相似的基因组，转录组和信号通路在子宫内膜异位症和 猕猴腹膜和卵巢肿瘤与女性发现的相匹配的病变相关。结果是 将用于发展与俄勒冈州、加利福尼亚州、西南部和杜兰国家大学的网络 灵长类动物研究中心将猕猴作为卵巢癌的模型。此网络将可用 给所有研究人员，以研究卵巢癌的生物学以及测试新的诊断和治疗方法 在临床试验中测试之前在恒河猴身上的方法。

Abstract Epithelial ovarian cancer is a deadly disease with no effective treatment. The cancer is typically detected at advanced stages when it is already unresponsive to therapy. Therefore, there is an immediate need to define the biology of this cancer and develop novel methods for early diagnosis and therapies. Genetically modified mice or rodents grafted with tumor cell lines are the only mammalian models available to study ovarian cancer. Mice do not spontaneously develop ovarian cancer or its precursor lesions. A significant proportion of high grade serous ovarian carcinoma develops from transformed secretory fallopian tube epithelium that implants on the outer surface of the ovaries. In mice, the ovaries are encased in the bursa and therefore are not able to truly mimic the implantation of the tumors on the human ovarian surface. Other major subtypes of ovarian cancer, clear cell and endometrioid carcinomas originate from endometriotic lesions. Endometriosis is not a disease that spontaneously occurs in mice. These differences indicate that there is a need for a higher order animal model that is more representative of the anatomy and physiology in humans. More desirable will be a model where the ovarian tumors or at least its precursor lesions occur spontaneously. In this grant application we propose that the rhesus macaque can be developed into a model that is a better mimic of the three major subsets of ovarian cancer. The rhesus anatomy and endocrine physiology is highly similar to women and endometriosis is a spontaneously occurring condition. We have identified ovarian and peritoneal neoplasia in rhesus with endometriosis suggesting the possibility that these tumors may be spontaneously occurring clear cell or endometrioid ovarian carcinomas. The goal of this proposal therefore is to develop the rhesus as a model for the major subtypes of ovarian cancer. In Aim 1, we will conduct an immunohistological survey from the proximal to distal ends of the rhesus fallopian tubes to identify precursor lesions of high grade serous tumors. In Aim 2, we will demonstrate similarities in the genome, transcriptome, and signaling pathways in endometriosis and associated peritoneal and ovarian neoplasms of rhesus with the matching lesions found in women. The results of this proposal will be used to develop a network with the Oregon, California, Southwest and Tulane National Primate Research Centers to establish the rhesus as a model for ovarian cancer. This network will be available to all researchers to study the biology of ovarian cancer as well as to test novel diagnostic and therapeutic approaches in the rhesus prior to testing in clinical trials.