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.

抽象的 上皮卵巢癌是一种致命的疾病，没有有效治疗。通常在 高级阶段已经对治疗没有反应。因此，有立即定义的需要 这种癌症的生物学并开发了早期诊断和疗法的新方法。转基因 用肿瘤细胞系接枝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。 小鼠不会自发发展卵巢癌或其前体病变。高级比例很大 浆液卵巢癌是由植入在 卵巢的外表面。在老鼠中，卵巢被包裹在囊中，因此无法真正 模仿肿瘤在人卵巢表面上的植入。卵巢癌的其他主要亚型， 透明细胞和子宫内膜细胞癌来自子宫内膜损伤。子宫内膜异位症不是一种疾病 自发发生在小鼠中。这些差异表明需要高阶动物模型 这更代表了人类的解剖结构和生理学。更理想的是一个模型 卵巢肿瘤或至少其前体病变自发发生。在此赠款申请中，我们建议 恒河猕猴可以发展为一个模型，该模型是卵巢三个主要子集的更好模仿 癌症。恒河-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 自发发生条件。我们已经确定了恒河猴的卵巢和腹膜肿瘤 子宫内膜异位症表明这些肿瘤可能自发地发生透明细胞或 子宫内膜类药物卵巢癌。因此，该提案的目的是发展恒河猴作为模型 卵巢癌的主要亚型。在AIM 1中，我们将对近端进行免疫组织学调查 输卵管恒河管的远端，以鉴定高级浆液肿瘤的前体病变。在AIM 2中，我们 将在基因组，转录组和子宫内膜异位症和信号通路中表现出相似性 恒河的相关腹膜和卵巢肿瘤与妇女中发现的匹配病变。结果 该提案将用于与俄勒冈州，加利福尼亚州，西南和图兰国家国家建立网络 灵长类动物研究中心将恒河从卵巢癌建立为模型。该网络将可用 对于所有研究人员，研究卵巢癌的生物学以及测试新型诊断和治疗性 在临床试验中进行测试之前，恒河猴的方法。