Development and validation of preclinical mouse model for serous ovarian cancer

浆液性卵巢癌临床前小鼠模型的开发和验证

• 批准号: 8349495
• 负责人: Terry van Dyke
• 金额: $ 144.91万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349495
• 关键词: Age; Alleles; Animal Model; Animals; Ascites; BRCA1 gene; Benign; Bioinformatics; Biological Markers; Biology; Blood; CCR; Cancer Model; Cancerous; Carcinoma; Clinical; Collaborations; Collection; Companions; Data; Detection; Development; Diagnostic; Disease; Disease Progression; Epithelial; Epithelial Cells; Event; Gene Mutation; Genetic; Genetic Induction; Genetically Engineered Mouse; Goals; Histologic; Human; Image; Immunocompetent; Individual; Infection; Investigation; Liquid substance; Malignant Neoplasms; Malignant neoplasm of ovary; Manuscripts; Metabolic; Metastatic to; Mining; Modeling; Molecular; Molecular Profiling; Mus; Mutagenesis; North Carolina; Oncogenic; Operative Surgical Procedures; Outcome; Ovarian; Ovarian Carcinoma; Ovary; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phase; Preclinical Drug Evaluation; Preparation; Primary Cell Cultures; Production; Prognostic Marker; Prospective Studies; Publishing; Research Design; Route; Sampling; Scientist; Serous; Staging; System; Tamoxifen; Testing; The Cancer Genome Atlas; Therapeutic; Time; Tissue Sample; Tissues; Translating; Transplantation; Universities; Validation; Viral; base; cancer cell; cancer type; carcinogenesis; clinically relevant; cohort; comparative; cost; design; gene transfer vector; improved; model development; mouse model; neoplastic cell; novel; ovarian neoplasm; pre-clinical; preclinical efficacy; progression marker; recombinase; research and development; research study; response; scale up; tumor; tumor progression; tumorigenesis; tumorigenic

CAPR is establishing a genetically engineered mouse model of serous epithelial ovarian carcinoma. The loxP/Cre system is used to perturb the Rb, p53 and/or the Brca1 and Brca2 pathways specifically in the ovaries (Fig. 1). Currently, different induction systems are being tested to determine the most optimal design of serous ovarian cancer model applicable both for mining the basic biology of tumorigenesis in cancer type and subsequently for preclinical drug evaluation: 1) Adeno-Cre infection into the bursa of the ovary by survival surgery at 6 weeks of age. 2) Genetic induction using a tamoxifen-inducible MisIIR-CreER system. 3) Orthotopic transplantation of primary ovarian epithelial cells or ovarian tumor cells into the bursa of syngeneic mice. Preliminary data showed that the combined deletion of Brca1, p53 and the Rb pathway components using adenoviral induction leads to metastatic ovarian cancer with ascites by 10 months post-induction. The impact of genetic mutations and combinations thereof on the onset and progression of the disease is currently being analyzed. Prospective studies are designed to track biomarkers and improve imaging strategies that could be clinically translated and applied for early disease detection. Tumor samples will be subject to cross species omic analyses of human and mouse cancers to identify common molecular signatures that could provide new druggable targets for cancer therapeutics. In the second phase of this project, all three tumor induction approaches will be compared for their applicability for the production of large cohorts for preclinical efficacy determination. As a pilot experiment, the Research and Model Development team of CAPR induced a large cohort of animals featuring several combination of genetic events (pRb inactivation, p53 inactivation and somatically induced mutagenesis, BRCA1/2 inactivation). The induction had been performed via intra-bursa administration of adenovirally transduced Cre recombinase. This cohort of approximately 800 animals developed various stages of ovarian malignancy allowing CAPR scientists to undergo in-depth patho-histologic investigation of resulting tumors, as well as to collect blood, ascites and cancerous vs. benign tissue samples for molecular analyses and establishing primary cell cultures. Collected data are currently analysed by modern bioinformatics approaches by the CCR Bioinformatics Core or in collaboration with Drs. Kohn's and Annunziata's clinical groups. In parallel, in collaboration with Dr. Van Dyke's previous lab at the University of North Carolina, a manuscript is in preparation, describing this specific genetic approach to model the metastatic serous ovarian cancer and molecular observations related to SEOC tumor progression and histopathologic attributes.

CAPR 正在建立浆液性上皮性卵巢癌的基因工程小鼠模型。 loxP/Cre 系统用于干扰 Rb、p53 和/或 Brca1 和 Brca2 通路，特别是在卵巢中（图 1）。 目前，正在测试不同的诱导系统，以确定浆液性卵巢癌模型的最佳设计，该模型既适用于挖掘癌症类型肿瘤发生的基础生物学，也适用于随后的临床前药物评估：1）通过 6 周龄生存手术将 Adeno-Cre 感染到卵巢囊中。 2) 使用他莫昔芬诱导型 MisIIR-CreER 系统进行遗传诱导。 3)将原代卵巢上皮细胞或卵巢肿瘤细胞原位移植到同基因小鼠的法氏囊中。初步数据显示，通过腺病毒诱导联合删除 Brca1、p53 和 Rb 通路成分，可在诱导后 10 个月导致转移性卵巢癌伴腹水。目前正在分析基因突变及其组合对疾病发生和进展的影响。前瞻性研究旨在追踪生物标志物并改进成像策略，这些策略可以临床转化并应用于早期疾病检测。肿瘤样本将接受人类和小鼠癌症的跨物种组学分析，以确定共同的分子特征，从而为癌症治疗提供新的药物靶点。在该项目的第二阶段，将比较所有三种肿瘤诱导方法对于产生大型队列以进行临床前疗效测定的适用性。 作为一项试点实验，CAPR 的研究和模型开发团队诱导了一大群具有多种遗传事件组合（pRb 失活、p53 失活和体细胞诱导突变、BRCA1/2 失活）的动物。通过腺病毒转导的Cre重组酶的囊内施用进行诱导。这组大约 800 只动物出现了不同阶段的卵巢恶性肿瘤，使 CAPR 科学家能够对由此产生的肿瘤进行深入的病理组织学研究，并收集血液、腹水和癌性与良性组织样本进行分子分析和建立原代细胞培养物。目前，CCR 生物信息学核心或与 Drs. 合作，通过现代生物信息学方法对收集的数据进行分析。 Kohn 和 Annunziata 的临床组。 与此同时，与 Van Dyke 博士之前在北卡罗来纳大学的实验室合作，正在准备一份手稿，描述这种用于模拟转移性浆液性卵巢癌的特定遗传方法以及与 SEOC 肿瘤进展和组织病理学属性相关的分子观察。