Can be adapted in scope for Honours or PhD project.
Epithelial ovarian cancer (EOC) accounts for >90% of ovarian malignancies, but high-grade serous (HGSOC) is the most common (~70%) and lethal subtype. Nearly half of all HGSOCs show defective DNA repair by homologous recombination (HR), which is a pivotal vulnerability that can be therapeutically exploited. Platinum-based chemotherapy and PARP inhibitor (PARPi) therapy are currently the most effective therapeutic options for HR-deficient HGSOCs. However, while initial response rates to both therapies are high, most patients relapse due to the emergence of chemoresistant disease, typically through the restoration of HR repair. Most studies focus on targeting protein-coding genes to increase therapeutic sensitivity, with limited clinical success. However, long noncoding RNAs (lncRNAs) also play important roles in the DNA damage response.
In this project, we will discover, annotate and prioritise new lncRNAs involved in DNA repair in HGSOC. We will then perform high-throughput CRISPR-based screens to identify specific lncRNAs that enhance PARPi sensitivity. We will also perform multiple functional assays on the lncRNAs that showed the strongest effect in the CRISPR-based screens. These include generating isogenic cell lines using CRISPR technology, which will be used to measure lncRNA expression, perform clonogenic survival assays and measure DNA repair efficiency or kinetics. Finally, we will assess the potential of antisense oligonucleotides (ASOs) to inhibit the expression or function of the lncRNAs in HGSOC cell lines and using established PDX models in mice. We predict that ASOs in combination with PARPi, will make initial treatment of patients more effective and reduce HGSOC recurrence.
Students will have access to unique expertise and reagents, and will acquire skills in tissue culture, CRISPR methods, RNA manipulation, and other basic molecular biology techniques.