Ovarian cancer is the major cause of death from gynaecological cancers. The most common and aggressive subtype, high-grade serous ovarian cancer (HGSOC), accounts for 70-80% of all ovarian cancer deaths. HGSOC patients are treated by surgery and/or chemotherapy, yet within 5 years most women experience cancer relapse, making the development of new treatment options an essential priority.
We have shown that CX-5461, the novel inhibitor of RNA polymerase I (Pol I) transcription of ribosomal RNA genes, exhibits therapeutic efficacy in ovarian cancer models. CX-5461 has shown promising activity in Phase I clinical trials in blood and solid cancers. Our studies demonstrate CX-5461 induces a localised DNA damage response (DDR) within the nucleoli, the site of Pol I transcription. This unique nucleolar DDR (n-DDR) is distinct to DDR initiated by DNA damaging agents. n-DDR and nucleolar stress cause global replication stress via destabilising replication forks leading to activation of cell cycle checkpoints. But how activation of nucleolar stress leads to destabilisation of replication forks remains an unresolved question. Importantly, our studies demonstrate substantial efficacy for CX-5461 in chemotherapy-resistant models of HGSOC.
Our research aims to understand how n-DDR and nucleolar stress lead to global replication stress. This project will aid the discovery of novel therapeutic targets and treatment strategies for relapsed ovarian cancer. This project also aims to investigate the molecular mechanisms underlying the improved efficacy of CX-5461 in combination with DNA repair and DNA damage response inhibitors against ovarian cancer. Specifically, we aim to characterise the molecular and cellular response to CX-5461 in combination with PARPi and cisplatin (chemotherapy) in primary and cancer ovarian cell lines.