Ovarian cancer is the fifth leading cause of female cancer-related death in the UK, accounting for over 4,000 UK deaths and ~185,000 deaths globally in 2018. The most prevalent subtype, high-grade serous ovarian carcinoma (HGSOC) is particularly lethal because it develops rapidly and often presents at an advanced stage. Treatment options are limited; typically, cytoreductive surgery and paclitaxel/platinum-based chemotherapy, maintenance therapy and hormone antagonists. While many patients initially respond well, most develop recurrent disease, yielding 10-year survival rates of about 35%.
HGSOC is characterised by ubiquitous TP53 mutation and extensive copy number variation (CNV). BRCA1/BRCA2 are inactivated in ~20% of cases, leading to homologous recombination deficiency (HRD), however DNA damage repair (DDR) defects are more widespread. Extensive CNV implies chromosome instability, and indeed, HGSOC is one of the most chromosomally unstable cancers.
While precision medicine is revolutionising cancer treatment, this paradigm is challenging in HGSOC due to the paucity of actionable driver mutations. Other therapeutic strategies are therefore required and indeed, HRD has opened up an alternative, namely synthetic lethality. This approach was pioneered by the ability of PARP inhibitors (PARPi) to selectively kill BRCA-mutant cells, and these drugs are now yielding major benefits for women with BRCA-mutant ovarian cancer.
While only ~20% of HGSOC cases have BRCA1/2 mutation, a further ~30% are HRD due to other oncogenic lesions and thus might also benefit from PARPi. This still leaves up to ~50% of HGSOC cases that are HR-proficient and unlikely to benefit from a PARPi-based strategy. This leads to our central question: how can we improve outcomes for women with HR-proficient disease?
Our hypothesis is that HR-proficient tumours have other cell cycle vulnerabilities that can be exploited, and to test this hypothesis, we are applying a multi-disciplinary approach focusing on several interconnected cell-cycle-related processes implicated in tumourigenesis, namely MYC overexpression, replication stress and aberrant mitoses. Our vision is that by generating new knowledge into the underlying biology of HGSOC we will be able to develop biomarker-driven strategies for patients with HR-proficient ovarian cancer.