Expanding the scope of PARPi for treatment of high-grade serous ovarian cancers

Suitable for Honours or PhD students.

In Australia, approximately 1600 women are diagnosed with ovarian cancer each year and the majority have high-grade serous ovarian type (HGSOC). Five years survival rate for ovarian cancer is currently just 41% and lags well behind breast (91% survival) and other cancers. Notably, resistance to standard of care chemotherapy is a common occurrence associated with multiple mechanisms and a poor prognosis of less than 12 months. Thus, development of novel strategies to overcome treatment resistance in HGSOC remains an urgent and unmet clinical need.

Not all HGSOCs are the same, based on expression of different genes, four distinct subtypes with unique clinical outcomes have been identified.  Notwithstanding, MYC amplification or activation, linked with tumour aggressiveness, are found in over 50% of HGSOCs. The development of direct inhibitors of MYC has been unsuccessful, with none in routine clinical use. Inhibition of genes/ pathways that regulate MYC oncogenic activity is emerging as an efficient strategy to treat MYC-driven cancers. We have identified an upstream regulator of MYC activity in HGSOCs and we have compelling data that a novel inhibitor, suppresses homologous recombination (HR) repair of DNA damage, can be repurposed for therapeutic targeting of HGSOCs in combination with PARPi in BRCA1/2 wildtype and BRCA1/2 mutant patient-derived HGSOC tumours that have acquired resistance to PARPi. The positive outcomes of this work will therefore not only benefit patients with BRCA1/2 mutation who has progressed on PARPi but also provide a new treatment strategy for the majority of patients who do not carry BRCA1/2 mutation.