Developing non-human primate models for ovarian cancer

开发卵巢癌的非人类灵长类动物模型

• 批准号: 10044729
• 负责人: Manish S Patankar
• 金额: $ 39.92万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-14 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044729
• 关键词: Anatomy; Animal Model; Animals; Applications Grants; Biology; CA-125 Antigen; CRISPR/Cas technology; California; Cancer Biology; Carcinoma in Situ; Clear Cell; Clinical; Clinical Trials; Collaborations; Copy Number Polymorphism; DNA sequencing; Data; Databases; Development; Diagnosis; Disease; Distal; Early Diagnosis; Early treatment; Endocrine Physiology; Endometrioid Carcinoma; Epithelial; Epithelial cyst; Epithelial ovarian cancer; Epithelium; Estrogen Receptors; Estrous Cycle; Female; Future; Genes; Genome; Genotype-Tissue Expression Project; Goals; Human; Implant; In Vitro; Investigation; Lesion; Macaca; Macaca mulatta; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Menstrual cycle; Methods; Modeling; Monitor; Mus; Mutation; Neoplasms; Oregon; Ovarian; Ovarian Carcinoma; Ovarian Clear Cell Tumor; Ovarian Endometrioid Adenocarcinoma; Ovarian Serous Adenocarcinoma; Ovary; PIK3CA gene; PTEN gene; Pathologic; Pathology; Patients; Peritoneal; Peritoneal Neoplasms; Physiological; Physiology; Primates; Protocols documentation; Records; Research; Research Personnel; Resources; Rhesus; Rodent; Serous; Signal Pathway; Stains; Study models; Surface; Surveys; TP53 gene; Technical Expertise; Testing; The Cancer Genome Atlas; Tissues; Translations; Tube; Tumor Cell Line; WFDC2 gene; WT1 gene; Wisconsin; Woman; cancer subtypes; cancer therapy; driver mutation; effective therapy; endometriosis; human tissue; implantation; intraepithelial; mouse model; mutant; nonhuman primate; novel; novel diagnostics; novel therapeutic intervention; novel therapeutics; ovarian neoplasm; pre-clinical; programs; reproductive tract; transcriptome; transcriptome sequencing; transcriptomics; tumor

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.

摘要 卵巢上皮癌是一种致命的疾病，没有有效的治疗方法。癌症通常在 当它已经对治疗无反应时，它处于晚期阶段。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 移植有肿瘤细胞系的小鼠或啮齿动物是研究卵巢癌的唯一可用的哺乳动物模型。 小鼠不会自发发展卵巢癌或其前驱病变。很大一部分高等级 浆液性卵巢癌是由转化的分泌性输卵管上皮细胞发展而来， 卵巢的外表面。在小鼠中，卵巢被囊包裹，因此不能真正地 模拟肿瘤在人类卵巢表面的植入。卵巢癌的其他主要亚型， 透明细胞癌和类胶质细胞癌起源于类胶质细胞病变。子宫内膜异位症不是一种 在小鼠中自发发生。这些差异表明需要更高阶的动物模型 更能代表人类的解剖学和生理学。更可取的是一种模式， 卵巢肿瘤或至少是其前体病变自发发生。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癌的三个主要亚群的模型， 癌恒河猴的解剖学和内分泌生理学与女性高度相似，子宫内膜异位症是一种 自然发生的情况。我们已经确定了恒河猴卵巢和腹膜肿瘤， 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 卵巢恶性肿瘤因此，本提案的目标是将恒河猴作为 卵巢癌的主要亚型。在目标1中，我们将从近端到远端进行免疫组织学调查。 恒河猴输卵管的远端，以确定高级别浆液性肿瘤的前驱病变。在目标2中， 将展示子宫内膜异位症的基因组、转录组和信号通路的相似性， 恒河猴的相关腹膜和卵巢肿瘤与女性中发现的匹配病变。结果 该提案的一部分将用于开发与俄勒冈州、加州、西南和杜兰国家队的网络 灵长类动物研究中心建立恒河猴作为卵巢癌模型。该网络将提供 所有研究人员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中的方法。