Investigating sequential and combined treatments of carboplatin and PARP inhibitors using three-dimensional culture models of advanced high-grade serous ovarian cancer
Jennifer Davis1,2, Emily Tomas2,3, Yudith Ramos Valdes2, Gabriel E DiMattia2,4,5, Jacob McGee6, Trevor G Shepherd2,3,4,6.
1Schulich School of Medicine and Dentistry, Western University, London, ON, Canada; 2Mary & John Knight Translational Ovarian Cancer Research Unit, London Regional Cancer Program, London, ON, Canada; 3Anatomy & Cell Biology, Western University, London, ON, Canada; 4Oncology, Western University, London, ON, Canada; 5Biochemistry, Western University, London, ON, Canada; 6Obstetrics and Gynaecology, Western University, London, ON, Canada
Introduction
Epithelial ovarian cancer is a deadly gynecological malignancy with an insidious disease onset and inadequate treatment options. PARP inhibitors (PARPi) are a targeted therapy that uses a synthetic lethal strategy to exploit homologous recombination repair deficiencies, which are present in over half of high-grade serous epithelial ovarian cancer (HGSOC) cases. Olaparib and niraparib are currently approved as maintenance therapy in platinum-sensitive HGSOC, and their utility in the neoadjuvant setting is recently under investigation. Thus, our objective is to determine the utility of PARPis as sequential or combination therapy with standard-of-care chemotherapy, carboplatin.
Methods
Ascites-derived malignant cells from eight patients with HGSOC who underwent cytoreductive surgery at London Health Sciences Centre have been established as new cell lines in adherent conditions. Tumour cells were grown as organoids in defined culture conditions, then drug treatments with PARPi (i.e., olaparib or niraparib) and carboplatin in combination or sequence were applied.
Results
The IC50 values for treatment with olaparib and niraparib are heterogeneous across cell lines and variable between two inhibitors. A BRCA1 mutant line showed sensitivity to both drugs, while other lines showed resistance. Organoid experiments with combination treatment of carboplatin and olaparib have shown increased tumour cell killing. However, sequential treatments revealed variable effectiveness dependent upon the order of agent used. Homologous recombination repair deficiency status of the cell lines will be pursued to identify potential biomarkers for optimal treatment sequencing of PARPi and carboplatin.
Conclusions
Ex vivo patient-derived tumour models could inform future clinical trials testing PARPi in the neoadjuvant setting for women diagnosed with advanced high-grade serous ovarian cancer.
We acknowledge funding from Ovarian Cancer Canada and Health Canada. J Davis was supported by the Mach-Gaensslen Foundation of Canada through the Summer Research Training Program at the Schulich School of Medicine and Dentistry..