Pathway-Specific Engineered Mouse Allograft Models Functionally Recapitulate Human Serous Epithelial Ovarian Cancer
Open accessAbstract
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.
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Conditional knockout mice, using the Cre-lox system for cell type specificity, have been used to reproduce oncogenic mutations and homologous recombination defects to study ovarian cancer development and responses to clinically relevant treatments such as platinum-based drugs and PARP inhibitors.
“Conditional knockout mice, using the Cre-lox system for cell type specificity, have been used to reproduce oncogenic mutations and HR defects to study ovarian cancer development and responses to clinically relevant treatments such as platin-based drugs and PARPis (Szabova et al., 2012; Perets et al., 2013; Szabova et al., 2014; Zhai et al., 2017).”
From Three-dimensional modelling of ovarian cancer: from cell lines to organoids for discovery and personalized medicine (2022) · cites this paper as Szabova et al., 2014
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- Authors
- Szabova, L., Bupp, S., Kamal, M., Householder, D. B., Hernandez, L., Schlomer, J. J., Baran, M. L., Yi, M., Stephens, R. M., Annunziata, C. M., Martin, P. L., Van Dyke, T. A., Ohler, Z. W., & Difilippantonio, S.
- Affiliations
- Frederick National Laboratory for Cancer Research (US)
- National Institutes of Health (US)
- Corresponding author
- Szabova, Ludmila
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-04-18
- Volume
- 9
- Issue
- 4
- Pages
- e95649
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3991711
- OpenAlex
- W2044107478
- Cited by
- 25
- References
- 47
- Citations by year
- 2026: 3 · 2025: 2 · 2023: 4 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 4 · 2016: 1 · 2015: 4
- FWCI
- 2.02
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- U.S. Department of Health and Human Services (HHSN261200800001E)
- Leidos (HHSN261200800001E)
- National Institutes of Health (#HHSN261200800001E, HHSN261200800001C)
- National Cancer Institute (HHSN261200800001E))
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- serous epithelial ovarian cancer, genetically engineered mouse models, BRCA1, BRCA2, TP53, Rb, cisplatin, olaparib, PARP inhibitors, platinum resistance, preclinical cancer models, drug response prediction, biomarkers
- MeSH terms
- Carcinoma, Ovarian Epithelial, Animals, Antineoplastic Agents, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Humans, Mutation, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Cluster Analysis, Cystadenocarcinoma, Serous, Disease Progression, Drug Resistance, Neoplasm, BRCA1 Protein, Gene Expression Profiling, Cell Line, Tumor, Tumor Burden, Mice, Allografts
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