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Activation of nucleolar-specific DNA damage response as a therapeutic strategy for ovarian cancer

Masters/Honours project

Ovarian cancer is the major cause of death from gynecological cancers. The most common and aggressive subtype, high-grade serous ovarian cancer (HGSOC), accounts for 70-80% of all ovarian cancer deaths. HGSOC patients are treated by surgery and/or chemotherapy, yet within 5 years most women experience cancer relapse making the development of new treatment options an essential priority.
We developed a “first in class” drug, CX-5461 that inhibits RNA polymerase I transcription of ribosomal RNA genes and induces high levels of stress and growth arrest in cancer cells. CX-5461 is demonstrating promising activity in early phase clinical trials in haematologic and solid cancers. We have shown that CX-5461 activates the DNA damage response at the ribosomal RNA genes within the nucleoli leading to global DNA replication stress in HGSOC cells. Importantly, our studies demonstrate substantial efficacy for CX-5461 in chemotherapy-resistant models of HGSOC.
50% of HGSOC is characterized by frequent alterations of genes involved in the homologous recombination (HR) DNA repair pathway. Aberrations in DNA repair provide a weakness that can be exploited therapeutically with genotoxic chemotherapy and inhibitors of DNA repair such as PARP inhibitors (PARPi), now approved in the clinic. Our data demonstartes that CX-5461 in combination with PARPi has significant therapeutic benefit in HGSOC pre-clinical models. This project aims to investigate the molecular mechanisms underlying the improved efficacy of CX-5461 in combination with DNA repair and DNA damage response inhibitors against ovarian cancer. Specifically, we aim to characterise the molecular and cellular response to CX-5461 in combination with PARPi and cisplatin (chemotherapy) in primary and cancer ovarian cell lines.

Supervised by:

  • A/Prof Elaine Sanij
  • Disease Focus:

  • Cancer
  • Research Unit:

  • DNA damage & cancer therapy
  • For further information about this project, contact: [email protected]