A patient-derived-xenograft platform to study BRCA-deficient ovarian cancers. George, E., Kim, H., Krepler, C., Wenz, B., Makvandi, M., Tanyi, J. L., Brown, E., Zhang, R., Brafford, P., Jean, S., Mach, R. H., Lu, Y., Mills, G. B., Herlyn, M., Morgan, M., Zhang, X., Soslow, R., Drapkin, R., Johnson, N., Zheng, Y., Cotsarelis, G., Nathanson, K. L., & Simpkins, F. JCI insight, 2(1):e89760, January, 2017. ![A patient-derived-xenograft platform to study BRCA-deficient ovarian cancers [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex Approximately 50% of high-grade serous ovarian cancers (HGSOCs) have defects in genes involved in homologous recombination (HR) (i.e., BRCA1/2). Preclinical models to optimize therapeutic strategies for HR-deficient (HRD) HGSOC are lacking. We developed a preclinical platform for HRD HGSOCs that includes primary tumor cultures, patient-derived xenografts (PDXs), and molecular imaging. Models were characterized by immunohistochemistry, targeted sequencing, and reverse-phase protein array analysis. We also tested PDX tumor response to PARP, CHK1, and ATR inhibitors. Fourteen orthotopic HGSOC PDX models with BRCA mutations (BRCA(MUT)) were established with a 93% success rate. The orthotopic PDX model emulates the natural progression of HGSOC, including development of a primary ovarian tumor and metastasis to abdominal viscera. PDX response to standard chemotherapy correlated to that demonstrated in the patient. Pathogenic mutations and HGSOC markers were preserved after multiple mouse passages, indicating retention of underlying molecular mechanisms of carcinogenesis. A BRCA2(MUT) PDX with high p-CHK1 demonstrated a similar delay of tumor growth in response to PARP, CHK1, and ATR inhibitors. A poly (ADP-ribose) polymerase (PARP) inhibitor radiotracer correlated with PARP1 activity and showed response to PARP inhibition in the BRCA2(MUT) PDX model. In summary, the orthotopic HGSOC PDX represents a robust and reliable model to optimize therapeutic strategies for BRCA(MUT) HGSOC.
@article{george_patient-derived-xenograft_2017,
title = {A patient-derived-xenograft platform to study {BRCA}-deficient ovarian cancers},
volume = {2},
url = {https://insight.jci.org/articles/view/89760},
doi = {10.1172/jci.insight.89760 [doi]},
abstract = {Approximately 50\% of high-grade serous ovarian cancers (HGSOCs) have defects in genes involved in homologous recombination (HR) (i.e., BRCA1/2). Preclinical models to optimize therapeutic strategies for HR-deficient (HRD) HGSOC are lacking. We developed a preclinical platform for HRD HGSOCs that includes primary tumor cultures, patient-derived xenografts (PDXs), and molecular imaging. Models were characterized by immunohistochemistry, targeted sequencing, and reverse-phase protein array analysis. We also tested PDX tumor response to PARP, CHK1, and ATR inhibitors. Fourteen orthotopic HGSOC PDX models with BRCA mutations (BRCA(MUT)) were established with a 93\% success rate. The orthotopic PDX model emulates the natural progression of HGSOC, including development of a primary ovarian tumor and metastasis to abdominal viscera. PDX response to standard chemotherapy correlated to that demonstrated in the patient. Pathogenic mutations and HGSOC markers were preserved after multiple mouse passages, indicating retention of underlying molecular mechanisms of carcinogenesis. A BRCA2(MUT) PDX with high p-CHK1 demonstrated a similar delay of tumor growth in response to PARP, CHK1, and ATR inhibitors. A poly (ADP-ribose) polymerase (PARP) inhibitor radiotracer correlated with PARP1 activity and showed response to PARP inhibition in the BRCA2(MUT) PDX model. In summary, the orthotopic HGSOC PDX represents a robust and reliable model to optimize therapeutic strategies for BRCA(MUT) HGSOC.},
language = {eng},
number = {1},
journal = {JCI insight},
author = {George, E. and Kim, H. and Krepler, C. and Wenz, B. and Makvandi, M. and Tanyi, J. L. and Brown, E. and Zhang, R. and Brafford, P. and Jean, S. and Mach, R. H. and Lu, Y. and Mills, G. B. and Herlyn, M. and Morgan, M. and Zhang, X. and Soslow, R. and Drapkin, R. and Johnson, N. and Zheng, Y. and Cotsarelis, G. and Nathanson, K. L. and Simpkins, F.},
month = jan,
year = {2017},
pmid = {28097235},
pmcid = {PMC5214535},
keywords = {CORE TBD},
pages = {e89760},
}
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We developed a preclinical platform for HRD HGSOCs that includes primary tumor cultures, patient-derived xenografts (PDXs), and molecular imaging. Models were characterized by immunohistochemistry, targeted sequencing, and reverse-phase protein array analysis. We also tested PDX tumor response to PARP, CHK1, and ATR inhibitors. Fourteen orthotopic HGSOC PDX models with BRCA mutations (BRCA(MUT)) were established with a 93% success rate. The orthotopic PDX model emulates the natural progression of HGSOC, including development of a primary ovarian tumor and metastasis to abdominal viscera. PDX response to standard chemotherapy correlated to that demonstrated in the patient. Pathogenic mutations and HGSOC markers were preserved after multiple mouse passages, indicating retention of underlying molecular mechanisms of carcinogenesis. A BRCA2(MUT) PDX with high p-CHK1 demonstrated a similar delay of tumor growth in response to PARP, CHK1, and ATR inhibitors. A poly (ADP-ribose) polymerase (PARP) inhibitor radiotracer correlated with PARP1 activity and showed response to PARP inhibition in the BRCA2(MUT) PDX model. 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