Related Experiment Video
Updated: Mar 8, 2026
Generation and Culturing of High-Grade Serous Ovarian Cancer Patient-Derived Organoids
Published on: January 6, 2023
A patient-derived-xenograft platform to study BRCA-deficient ovarian cancers
Erin George1, Hyoung Kim1, Clemens Krepler2
1Ovarian Cancer Research Center, Division of Gynecology Oncology, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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 (BRCAMUT) 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 BRCA2MUT 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 BRCA2MUT PDX model. In summary, the orthotopic HGSOC PDX represents a robust and reliable model to optimize therapeutic strategies for BRCAMUT HGSOC.
Insights
Researchers developed a new preclinical platform using patient-derived xenografts (PDXs) to test therapies for homologous recombination deficient (HRD) ovarian cancer. This reliable model helps optimize treatments for BRCA-mutated high-grade serous ovarian cancer (HGSOC).
Area of Science:
- Oncology
- Genetics
- Preclinical Research
Background:
- High-grade serous ovarian cancer (HGSOC) frequently exhibits defects in homologous recombination (HR) genes, such as BRCA1/2.
- Effective preclinical models are crucial for developing and optimizing therapeutic strategies for HR-deficient (HRD) HGSOC.
Purpose of the Study:
- To establish and characterize a robust preclinical platform for HRD HGSOC, including patient-derived xenografts (PDXs).
- To evaluate the utility of this platform in testing targeted therapies and molecular imaging agents for BRCA-mutated (BRCAMUT) HGSOC.
Main Methods:
- Development of fourteen orthotopic HGSOC PDX models from primary tumors of patients with BRCA mutations.
- Characterization using immunohistochemistry, targeted sequencing, and reverse-phase protein array analysis.
- Assessment of PDX response to PARP, CHK1, and ATR inhibitors, and evaluation of a PARP inhibitor radiotracer.
Main Results:
- A 93% success rate in establishing orthotopic HGSOC PDX models that mimic natural disease progression and metastasis.
- Preservation of key mutations and HGSOC markers across multiple passages, confirming molecular fidelity.
- Demonstrated efficacy of PARP, CHK1, and ATR inhibitors in a BRCA2MUT PDX model; PARP inhibitor radiotracer correlated with PARP1 activity.
Conclusions:
- The orthotopic HGSOC PDX platform is a reliable and effective preclinical tool for studying HRD ovarian cancer.
- This model system facilitates the optimization of therapeutic strategies, including targeted inhibitors and imaging agents, for BRCAMUT HGSOC.
