Credentialing Ovarian Cancer Models in the Context of the Dualistic Pathway Paradigm

在二元途径范式背景下验证卵巢癌模型

基本信息

批准号：
9260771
负责人：
KATHLEEN R. CHO
金额：
$ 48.91万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9260771
关键词：
Adenoviruses Alleles Bilateral Biological Biological Models Biology Blood Circulation Cancer Model Carcinoma Categories Cervical Cessation of life Characteristics Chromatin Remodeling Factor Chromosomal Instability Clinical Credentialing Data Defect Diagnosis Disease Distal Early Diagnosis Early treatment Enterobacteria phage P1 Cre recombinase Epithelium Excision Functional disorder Funding Opportunities Gene Expression Gene Mutation Genes Genetic Genetically Engineered Mouse Goals Human Human Biology Indolent Inherited Injection of therapeutic agent Lesion Liquid substance Location LoxP-flanked allele Malignant Female Reproductive System Neoplasm Malignant neoplasm of ovary Mammalian Oviducts Metastatic to Methods Microscopic Modeling Molecular Molecular Profiling Monitor Morphology Mouse Strains Mus Mutation Neoplasm Metastasis Operative Surgical Procedures Ovarian Ovarian Carcinoma Ovarian Endometrioid Adenocarcinoma Pap smear Pathogenesis Pathologic Pathway interactions Predisposition Prevention Primary Lesion Reporter Reporting Resolution Risk Reduction Salpingo-Oophorectomy Sampling Screening for Ovarian Cancer Serous Signal Pathway Signal Transduction Somatic Mutation Specimen Surface System TP53 gene Tamoxifen Technology Testing Transgenic Organisms Translational Research Tube Tumor Biology Tumor Suppressor Genes Tumor-Derived United States Vaginal Douching Validation Woman base bioluminescence imaging cancer risk cohort digital digital imaging imaging detection improved in vivo intraperitoneal mouse model mutant next generation sequencing oncology preclinical study promoter prophylactic public health relevance response tool translational study tumor tumor DNA tumor progression virtual

项目摘要

DESCRIPTION (provided by applicant): A dualistic model of ovarian cancer (OvCa) pathogenesis has recently been proposed in which OvCas can be broadly divided into two categories. Type I OvCas are considered to be low-grade, relatively indolent tumors, while Type II OvCas are high-grade, biologically aggressive tumors from their outset. Recent studies suggest the most common and lethal type of "ovarian" cancer, high-grade serous carcinoma (HGSC), usually arises in fallopian tube epithelium (FTE) rather than the ovarian surface epithelium (OSE). HGSCs display a high level of chromosomal instability and virtually all harbor somatic TP53 mutations, which occur very early in HGSC pathgenesis. Dysfunction of the RB and BRCA pathways is also common in HGSCs. Genetic instability in the early lesions presumably enhances the likelihood that somatic mutations conferring metastatic potential will be acquired. Thus, women with HGSCs typically have small primary lesions and widespread metastases at diagnosis. A current challenge is to detect early-stage HGSCs while they are curable with surgical resection. Genetically engineered mouse models (GEMMs) of OvCa that closely recapitulate their human tumor counterparts provide excellent in vivo systems with which to study tumor biology and perform pre-clinical studies aimed at improving prevention, early detection, and therapy for OvCa. Several GEMMs of OvCa based on OSE transformation have been developed and used in translational studies. More recently, a few models based on transformation of the FTE have been reported. It is not yet known whether oviductal (mouse fallopian tube) models of OvCa are superior to those arising from the OSE with respect to how well they recapitulate the biology of human OvCas or their utility for translational applications. We have developed a new GEMM that employs the Ovgp1 promoter to direct expression of Tamoxifen (TAM)-inducible Cre recombinase in the FTE. Ovgp1-iCreERT2 mice that also carry floxed alleles of tumor suppressor genes that are characteristically inactivated in ovarian endometrioid carcinoma (OEC, prototypical Type I tumor) and HGSC (prototypical Type II tumor) can be induced to form tumors in the FTE following treatment with TAM, or tumors arising in the OSE following ovarian bursal injection of adenovirus expressing Cre. The overarching goal of this funding opportunity is to enhance applicability of mouse models for translational research. Toward that end, we will pursue the following Specific Aims: 1) To credential GEMMs of OvCa arising from FTE- transformation as superior to those arising from OSE-transformation in terms of their morphological and molecular similarity to their human OvCa counterparts; and 2) To test a new tool strain for early detection of oviductal HGSCs based on cervical-vaginal lavage (murine Pap test). Comprehensive gene expression and mutation data with matched high-resolution digital images of murine OECs and HGSCs will be shared at the Oncology Models Forum via the NCIP Hub platform.

描述（由申请人提供）：最近提出了卵巢癌（OvCa）发病机制的二元模型，其中OvCas可大致分为两类：I型OvCas被认为是低级别、相对惰性的肿瘤，而II型OvCas被认为是低级别、相对惰性的肿瘤。 OvCas 从一开始就是高级别、具有生物侵袭性的肿瘤，最近的研究表明，最常见和致命的“卵巢”癌，即高级别浆液性癌 (HGSC)，通常出现在卵巢中。输卵管上皮 (FTE) 而不是卵巢表面上皮 (OSE) 表现出高度的染色体不稳定性，并且几乎所有的体细胞 TP53 突变都发生在 HGSC 发病的早期。RB 和 BRCA 途径的功能障碍也很常见。在 HGSC 中，早期病变的遗传不稳定性可能会增加体细胞突变赋予转移潜力的可能性。 HGSC 在诊断时通常具有较小的原发灶和广泛的转移，当前的挑战是检测早期 HGSC，同时可以通过手术切除来治愈它们，该模型密切再现了它们的人类肿瘤对，可提供出色的体内效果。已经开发了一些基于 OSE 转化的 OvCa GEMM 系统，用于研究肿瘤生物学并进行临床前研究，旨在改善 OvCa 的预防、早期检测和治疗。最近，一些基于 FTE 转化的模型已被报道，目前尚不清楚 OvCa 的输卵管（小鼠输卵管）模型是否优于 OSE 模型。它们概括了人类 OvCas 的生物学或其在翻译应用中的效用。我们开发了一种新的 GEMM，它采用 Ovgp1 启动子来指导他莫昔芬 (TAM) 诱导型 Cre 重组酶的表达。在 FTE 中，也携带肿瘤抑制基因的 floxed 等位基因，这些基因在卵巢子宫内膜样癌（OEC，典型的 I 型肿瘤）和 HGSC（典型的 II 型肿瘤）中被诱导形成肿瘤。 TAM 治疗后，或卵巢囊注射表达 Cre 的腺病毒后 OSE 中出现的肿瘤。为此，我们将追求以下具体目标：1) 证明 FTE 转化产生的 OvCa GEMM 在形态和结构方面优于 OSE 转化产生的 GEMM。 2) 测试一种新的工具菌株，用于基于宫颈阴道灌洗（鼠巴氏涂片）早期检测输卵管 HGSC测试）的综合基因表达和突变数据以及匹配的小鼠 OEC 和 HGSC 的高分辨率数字图像将通过 NCIP Hub 平台在肿瘤模型论坛上共享。