Ovarian cancer particularly high grade serous ovarian cancer (HGSOC) has poor prognosis and is one of the major causes of gynaecological cancer deaths, due to the lack of effective therapeutic options. Recently, the introduction of the Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi) has revolutionized the management of disease, being the only therapy introduced for HGSOC since chemotherapy agents were approved in the late 1980s. PARPi specifically targets homologous recombination (HR) DNA repair-deficient malignancies, leading to increased DNA damage and cancer cell death. However, since its introduction into the clinic the incidence of resistance to PARPi has been on the rise, with HR-deficient malignancies commonly regaining HR activity thereby making PARPi treatment ineffective; hence further investigation is needed to expand the utility of PARPi to HR-proficient disease. A novel small molecule inhibitor of RNA polymerase I transcription, CX-5461 has shown synthetic lethality against HR-deficient pre-clinical models of breast cancer and is currently in phase I clinical trial in haematological cancers at Peter Mac. By activating the DNA damage response (DDR), CX-5461 elicits a specific response within cancer cells resulting in cell death, cell cycle arrest and senescence. This project explores the efficacy of CX-5461 in the context of HGSOC and how activating the DDR may provide an opportunity for future combinations of CX-5461 with agents such as PARPi and immunotherapies. Utilising the mouse ovarian cancer cell line, ID8, we aim to firstly characterise the cellular and molecular in vitro response to CX-5461 including immune-modulatory responses. Preliminary, findings have demonstrated the synthetically lethality of CX-5461 with HR-deficient ID8 ovarian cancer cells whilst also demonstrating induction of the DDR. Furthermore, our aim is to investigate the efficacy of CX-5461 against ID8 tumours in vivo through establishing multiple derivative cell lines that mimic HR proficient, HR-deficient and PARPi resistance disease. At the conclusion, we envision the project will shed light on the potential and clinical relevance of CX-5461 for HGSOC treatment.