Poster Presentation 32nd Lorne Cancer 2020

Activation of nucleolar DNA damage response as a therapeutic strategy for ovarian cancer (#371)

Jiachen Xuan 1 , Natalie Brajanovski 1 , Keefe Chan 1 , Clare Scott 2 , Richard Pearson 1 , Elaine Sanij 1
  1. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Walter and Eliza Hall Institute, Melbourne, VIC, Australia

High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths worldwide and is characterized by genomic scarring with few driving oncogenes that can be therapeutically targeted. Approximately 50% of HGSOC harbour defects in homologous recombination (HR) DNA repair pathway, in particular BRCA1 and BRCA2. Chemotherapy and poly-ADP-ribose-polymerase (PARP) inhibitors are effective in HGSOC with defective HR. However, inherent and acquired resistance are common, thus emphasizing need for combination therapies and novel treatment strategies.

Our laboratory has developed CX-5461, a novel “first-in-class” inhibitor of RNA polymerase I transcription of ribosomal RNA genes, which has been shown to have on-target effects in hematologic malignancies1. CX-5461 is also in phase I clinical trial in solid tumors2 (Canadian Cancer Trials Group, NCT02719977).

Our lab has recently demonstrated CX-5461 exhibits single-agent efficacy in PARPi-sensitive and PARPi-resistant HGSOC patient-derived xenografts (PDX) in vivo. In this project, we have investigated the molecular and cellular response to CX-5461 in both isogenically matched HR-proficient and HR-deficient HGSOC cell lines. We have demonstrated synthetic lethality between CX-5461 and HR-deficiency in HGSOC, which is associated with replication stress leading to genomic instability. Our studies have also demonstrated that combination of CX-5461 with PARPi leads to DNA damage, pronounced cell cycle arrest and inhibition of clonogenic survival of HR-proficient HGSOC cells and exhibits greater efficacy in HR-deficient HGSOC cells. Importantly, we also provide evidence that CX-5461 has significant efficacy in PDX cells with reduced sensitivity to olaparib by overcoming fork protection. Our data therefore highlights the potential of CX-5461 therapy in primary and PARPi-resistant HGSOC.

Our current focus includes: 1) understanding the mechanisms of CX-5461-induced DNA damage response (DDR) including how localized nucleolar DDR converts to a global DDR response; and 2) Understanding the mechanisms underlying the cooperation between CX-5461 and PARPi in inhibiting survival of HGSOC cells. This will provide evidence for the potential of this combination therapy against HGSOC and facilitate clinical trials to improve patients’ outcome.

 

 

  1. Khot A, Brajanovski N, Cameron DP, Hein N, Maclachlan KH, Sanij E, et al. First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study. Cancer Discov. 2019;9(8):1036-49.
  2. Xu H, Di Antonio M, McKinney S, Mathew V, Ho B, O'Neil NJ, et al. CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours. Nat Commun. 2017;8:14432.