Pathway-specific engineered mouse allograft models functionally recapitulate human serous epithelial ovarian cancer

Area of Science:

• Oncology
• Genetics
• Preclinical Cancer Models

Background:

• High ovarian cancer mortality is linked to late diagnosis and treatment resistance.
• Platinum-based chemotherapy is standard but faces high resistance rates.
• Lack of predictive preclinical models hinders new drug development.

Purpose of the Study:

• To adapt genetically engineered mouse (GEM) models for ovarian cancer into orthotopic allografts.
• To create reliable preclinical models for evaluating novel therapeutics.
• To predict differential treatment responses in BRCA1-wild type and deficient tumors.

Main Methods:

• Generation of GEM models by perturbing Tp53, Rb, and Brca1/2.
• Adaptation of GEM models to orthotopic allografts.
• Treatment of tumors with cisplatin and olaparib (PARP inhibitor).

Main Results:

• Orthotopic allografts uniformly developed tumors with short latency.
• BRCA1-deficient tumors responded to cisplatin and olaparib.
• BRCA1-wild type tumors were non-responsive to these treatments.

Conclusions:

• Adapted GEM models accurately recapitulate human ovarian cancer characteristics.
• These models predict differential responses to chemotherapy and PARP inhibitors.
• The models are suitable for evaluating therapeutics and developing biomarkers for ovarian cancer.