ABSTRACT
The high mortality rate from ovarian cancers can be attributed to late-stage diagnosis and lack of effective treatment. Despite enormous effort to develop better targeted therapies, platinum-based chemotherapy still remains the standard of care for ovarian cancer patients, and resistance occurs at a high rate. One of the rate limiting factors for translation of new drug discoveries into clinical treatments has been the lack of suitable preclinical cancer models with high predictive value. We previously generated genetically engineered mouse (GEM) models based on perturbation of Tp53 and Rb with or without Brca1 or Brca2 that develop serous epithelial ovarian cancer (SEOC) closely resembling the human disease on histologic and molecular levels. Here, we describe an adaptation of these GEM models to orthotopic allografts that uniformly develop tumors with short latency and are ideally suited for routine preclinical studies. Ovarian tumors deficient in Brca1 respond to treatment with cisplatin and olaparib, a PARP inhibitor, whereas Brca1-wild type tumors are non-responsive to treatment, recapitulating the relative sensitivities observed in patients. These mouse models provide the opportunity for evaluation of effective therapeutics, including prediction of differential responses in Brca1-wild type and Brca1-deficient tumors and development of relevant biomarkers.
Subject(s)
Cystadenocarcinoma, Serous/genetics , Cystadenocarcinoma, Serous/metabolism , Neoplasms, Glandular and Epithelial/genetics , Neoplasms, Glandular and Epithelial/metabolism , Ovarian Neoplasms/genetics , Ovarian Neoplasms/metabolism , Allografts , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , BRCA1 Protein/genetics , Carcinoma, Ovarian Epithelial , Cell Line, Tumor , Cluster Analysis , Cystadenocarcinoma, Serous/drug therapy , Cystadenocarcinoma, Serous/mortality , Cystadenocarcinoma, Serous/pathology , Disease Models, Animal , Disease Progression , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm/genetics , Female , Gene Expression Profiling , Humans , Mice , Mutation , Neoplasms, Glandular and Epithelial/drug therapy , Neoplasms, Glandular and Epithelial/mortality , Neoplasms, Glandular and Epithelial/pathology , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Tumor Burden/drug effectsABSTRACT
The majority of human high-grade serous epithelial ovarian cancer (SEOC) is characterized by frequent mutations in p53 and alterations in the RB and FOXM1 pathways. A subset of human SEOC harbors a combination of germline and somatic mutations as well as epigenetic dysfunction for BRCA1/2. Using Cre-conditional alleles and intrabursal induction by Cre-expressing adenovirus in genetically engineered mice, we analyzed the roles of pathway perturbations in epithelial ovarian cancer initiation and progression. Inactivation of RB-mediated tumor suppression induced surface epithelial proliferation with progression to stage I carcinoma. Additional biallelic inactivation and/or missense p53 mutation in the presence or absence of Brca1/2 caused progression to stage IV disease. As in human SEOC, mice developed peritoneal carcinomatosis, ascites, and distant metastases. Unbiased gene expression and metabolomic profiling confirmed that Rb, p53, and Brca1/2-triple mutant tumors aligned with human SEOC, and not with other intraperitoneal cancers. Together, our findings provide a novel resource for evaluating disease etiology and biomarkers, therapeutic evaluation, and improved imaging strategies in epithelial ovarian cancer.
