Poster Presentation 30th Lorne Cancer Conference 2018

Targeting nucleolar DNA damage response as a novel therapeutic strategy for high-grade serous ovarian cancer (#255)

Elaine Sanij 1 2 , Katherine Hannan 3 , Jessica Ahern 1 , Shunfei Yan 1 4 , Jinbae Son 1 4 , Anthony Xuan 1 2 , Keefe Chan 1 , Karen Sheppard 1 5 , Ross Hannan 1 3 5 6 , Clare Scott 1 7 , Rick Pearson 1 4 5 6
  1. Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
  3. John Curtin School of Medical Research, Australian National University, Acton, ACT, Australia
  4. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
  5. Department of Biochemistry and Molecular biology, University of Melbourne, Melbourne, VIC, Australia
  6. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic
  7. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia

High-grade serous ovarian cancer (HGSOC) is characterised by genomic scarring with few driving oncogenes. Approximately 50% of HGSOCs are characterised by alterations of genes involved in the homologous recombination (HR) DNA repair pathway, most frequently BRCA1/21. HR deficient tumours are sensitive to platinum-based chemotherapy and Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi), however, resistance to therapy is associated with acquired HR proficiency. Thus, novel approaches that circumvent primary and acquired HR proficiency will provide a major advance in ovarian cancer therapy.

Cancer cells display high rates of ribosome synthesis. The ribosome is a complex of ribosomal RNAs (rRNA) and ∼78 ribosomal proteins. Hyperactivation of RNA polymerase I (Pol I) transcription of the rRNA genes is a consistent feature of cancer cells. We have demonstrated that inhibition of Pol I transcription using CX-5461 can selectivity kill cancer cells in vivo2-4. Our studies led to phase I clinical trials of CX-5461 in haematologic (Peter Mac) and breast cancers (Canada).

We recently demonstrated that CX-5461 activates a DNA damage response (DDR) specifically in the nucleoli, the site of Pol I transcription. Furthermore, the potency of CX-5461 in killing cancer cells in vivo is significantly enhanced in combination with DDR inhibitors5. Here we demonstrate that CX-5461 has substantial efficacy in HGSOC cell lines and that sensitivity to CX-5461 is associated with BRCA1 mutation gene signature. CX-5461 exhibits synthetic lethality with HR deficiency and has significant therapeutic efficacy in vivo in HR-deficient HGSOC patients-derived xenograft (PDX) models. Notably, CX-5461 in combination with PARPi has significant therapeutic benefit in HR-proficient HGSOC cells in vitro and PARPi-refractory PDXs in vivo. Thus, our data provide direct evidence for the effectiveness of this combination approach for the treatment of acquired HR-proficient HGSOC. Hence, a phase I/II trial of CX-5461 in HGSOC will be initiated at Peter Mac in 2018.

  1. Cancer Genome Atlas Research, N. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609-615 (2011).
  2. Bywater, M.J. et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer cell 22, 51-65 (2012).
  3. Devlin, J.R. et al. Combination therapy targeting ribosome biogenesis and mRNA translation synergistically extends survival in MYC-driven lymphoma. Cancer Discov 6(1), 59-70 (2015).
  4. Hein, N. et al. Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population. Blood 129(21):2882-2895 (2017).
  5. Quin, J. et al. Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling. Oncotarget 7(31), 49800-49818 (2016).