[HTML][HTML] A patient-derived-xenograft platform to study BRCA-deficient ovarian cancers

E George, H Kim, C Krepler, B Wenz, M Makvandi… - JCI insight, 2017 - ncbi.nlm.nih.gov
E George, H Kim, C Krepler, B Wenz, M Makvandi, JL Tanyi, E Brown, R Zhang, P Brafford…
JCI insight, 2017ncbi.nlm.nih.gov
Approximately 50% of high-grade serous ovarian cancers (HGSOCs) have defects in genes
involved in homologous recombination (HR)(ie, 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 …
Abstract
Approximately 50% of high-grade serous ovarian cancers (HGSOCs) have defects in genes involved in homologous recombination (HR)(ie, 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.
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