High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths. HGSOC is characterized by genomic scarring with relatively few driving oncogenes that can be therapeutically targeted. Approximately 50% of HGSOC are characterized by defects in the homologous recombination (HR) DNA repair pathway more frequently BRCA1/2. HR-deficient tumours are sensitive to chemotherapy and inhibition of additional DNA repair pathways, such as PARP inhibitors (PARPi). However, tumours frequently acquire resistance to therapy emphasising the need for novel combination therapies.
Hyperactivation of RNA polymerase I (Pol I) transcription of the ribosomal RNA genes to produce the ribosomal RNA components of the ribosome is a consistent feature of cancer cells. Our laboratory developed a “first in class” novel small molecule inhibitor of Pol I transcription CX-5461 that selectively kills cancer cells and is currently in phase I/II clinical trials in haematologic (Peter Mac) and breast cancers (Canada).
Importantly, our studies demonstrate the substantial efficacy of CX-5461 in HGSOC. Furthermore, our previous studies demonstrated that CX-5461 induces DNA damage response (DDR) within the nucleoli, raising the possibility of increasing the sensitivity of HGSOC to therapy by combining CX-5461 with chemotherapies or DDR inhibitors.
In this project, we aim to investigate the molecular and cellular response to CX-5461 in immortalised primary fallopian tube-derived cell line and HGSOC cell lines. In addition, we will examine the efficacy of CX-5461 in combination with cisplatin and small-molecule inhibitors of DDR including PARP, ATR, ATM, DNA-PK. We aim to provide evidence for the effectiveness of combination therapy to facilitate clinical trials that would improve HGSOC patient outcome.