Introduction: High-grade serous ovarian cancer (HGSOC) is the most aggressive subtype of ovarian cancer and accounts for the majority of all ovarian cancer deaths. Unfortunately, survival rates have shown little improvement within the last few decades which can attributed to the lack of actionable mutations and personalised strategies. PARP inhibitors are one of the few promising therapies that has shown good efficacy in HGSOCs with a BRCA1/2 mutation. However, resistance is almost inevitable and there is a need to provide therapy for patients with recurrent disease.
Previously, we have defined a clinical subset of patients that are characterised by having high cyclin E1 protein and BRCA1/2 mutation. From this, we have developed a synergistic therapy by combining CDK2 inhibitors with PARP inhibitors, initially applied in basal-like breast cancers. This project focuses on whether this combination therapy is effective in HGSOC as well as PARP inhibitor resistant HGSOC.
Objective: We aim to develop a personalised strategy to target this subset of HGSOC patients by combining CDK2 inhibitors with PARP inhibitors. Since PARP inhibitor resistance is common, we also aim to determine the effectiveness of this therapy on PARP inhibitor resistant disease.
Methods and Results: Combination therapy of CDK2 inhibitor and PARP inhibitor will be assessed across in vitro and in vivo models of HGSOC. Using an ID8 syngeneic mouse model, we have generated a resistance model by chronic exposure to PARP inhibitor. We will then demonstrate whether PARP inhibitor resistant cancers have restored PARP sensitivity when therapy is combined with CDK2 inhibition.
Conclusions: A significant factor in the large number of deaths from ovarian cancer is the lack of personalised treatment options. Our aim is to better understand and improve outcomes for HGSOC patients, especially the patient subset with high cyclin E1 protein and BRCA1/2 mutation.