DNA Damage & Cancer Therapy

Current research projects

• The nucleolar DNA damage response – A novel non-genotoxic approach to ovarian cancer therapy

  We have shown that CX-5461, the novel inhibitor of RNA polymerase I (Pol I) transcription of ribosomal RNA genes, exhibits therapeutic efficacy in ovarian cancer models. CX-5461 has shown promising activity in Phase I clinical trials in blood and solid cancers. Our studies demonstrate CX-5461 induces a localised DNA damage response (DDR) within the nucleoli, the site of Pol I transcription. This unique nucleolar DDR (n-DDR) is distinct to DDR initiated by DNA damaging agents. n-DDR and nucleolar stress cause global replication stress via destabilising replication forks leading to activation of cell cycle checkpoints (Sanij et al., Nature Comms 2020). How activation of nucleolar stress leads to destabilisation of replication forks remains an unresolved question. Our research aims to understand how nucleolar stress leads to global replication stress. This project will aid the discovery of novel therapeutic targets and treatment strategies for relapsed ovarian cancer.

  Reprogramming of mRNA translation as a driver of drug resistance in ovarian cancer

  Most women with high-grade serous ovarian cancer (HGSOC) will not survive for more than five years due to intrinsic resistance to the standard therapy or the rapid development of acquired resistance.

  Chemotherapy and PARP inhibitors (PARPi), the standard of care therapy in HGSOC, have been recently discovered to also act through deregulation of ribosome synthesis (ribosome stress) via inhibition of ribosomal RNA (rRNA) synthesis and ribosome biogenesis. In this study, we will investigate reprogramming of mRNA translation in response to chronic ribosome stress as a driver of drug resistance in HGSOC. We propose that delineating the mRNA translation landscape of resistant HGSOC will enable the identification of novel therapeutic targets and the design of more effective and durable therapies that will have significant impact for women with relapsed ovarian cancer.

  Investigating novel therapeutic strategies for multiple myeloma

  Proteasome inhibitors (PIs) have emerged as an important class of therapy for the treatment of multiple myeloma (MM), the second most common haematological malignancy. However, resistance to Pis is inevitable and represents an urgent clinical challenge.

  Resistance to Pis is linked to pro-survival pathways that protect cancer cells from cell death. We propose that the combination of Pis with therapies that target the ribosome, the “molecular machinery” responsible for protein synthesis, will improve therapeutic efficacy through inhibition of protein synthesis of pro-survival factors. The selective inhibitor of ribosome synthesis CX-5461 has recently demonstrated promising antitumor activity in heavily treated MM patients in an early Phase I clinical study. In this project, we will assess the effectiveness of targeting the ribosome in combination with the Pis in a MM mouse model. We will also characterise global protein signatures associated with resistance to Pis. Our findings will enable the identification of new therapeutic opportunities in targeting cellular pathways that are altered in resistant MM cells.