Poster Presentation 29th Lorne Cancer Conference 2017

Examining the potential of targeting ribosome biogenesis as a novel therapeutic strategy for ovarian cancer (#263)

Elaine Sanij 1 2 , Katherine M Hannan 3 , Jessica Ahern 1 , Jinbae Son 1 , Ross D Hannan 1 3 4 , Karen E Sheppard 1 5 , 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, Australia

Ovarian cancer (OVCA) is the major cause of death from gynaecological malignancy with the 5 year survival after diagnosis at ~43% due to resistance to chemotherapy. Thus, identification of new therapeutic strategies is essential to better treat this disease. The PI3K signaling pathway, the RAS/MEK/ERK pathway and the MYC transcription network are frequently deregulated in OVCA1. The PI3K/AKT/mTOR pathway is a key regulator of ribosome synthesis and function. We and others have shown that the RAS signaling pathway and MYC transcription network converge downstream of PI3K to confer coordinated control of ribosome biogenesis and protein translation2. Ribosome biogenesis involves synthesis ribosomal RNA (rRNA) by RNA Polymerase I (Pol I), synthesis of ribosomal proteins and the assembly of functional ribosomes. We have demonstrated that targeting ribosome biogenesis using a novel small molecule inhibitor of RNA polymerase I (Pol I) (CX-5461) can selectivity kill malignant cells in vivo3. CX-5461 is currently in first-in-class, phase 1 clinical trial in patients with haematological malignancies (Peter Mac). Very recently we have shown that the potency of CX-5461 in inhibiting ribosome biogenesis and killing cancer cells is significantly enhanced in combination with PI3K pathway inhibitors4. In addition, our studies demonstrate improved CX-5461 therapeutic efficacy in vivo when combined with inhibitors of DNA damage response5.

 

Given that a high proportion of ovarian cancers exhibit dysregulation of the pathways that control ribosome biogenesis, we propose that targeting this process will provide a novel therapeutic approach in OVCA. Pharmaco-genomic analysis of OVCA cells’ response to CX-5461 demonstrates that sensitivity to CX-5461 correlates with a DNA damage gene signature. Our data suggest strong synergy between CX-5461 and PARPi in vitro and we are currently validating the therapeutic efficacy of this combination in xenograft models. In summary, our research focuses on investigating the therapeutic efficacy of CX-5461 alone and in combination with standard and emerging targeted therapies that are in clinical trials and that are rationally selected based on extensive pharmaco-genomic and functional analysis of OVCA cells in vitro and in vivo as well as genomic analysis of primary human tumours.

  1. Cancer Genome Atlas Research, N. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609-615 (2011).
  2. Hannan, K.M., Sanij, E., Hein, N., Hannan, R.D. & Pearson, R.B. Signaling to the ribosome in cancer--It is more than just mTORC1. IUBMB Life 63, 79-85 (2011).
  3. 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).
  4. Devlin, J.R. et al. Combination therapy targeting ribosome biogenesis and mRNA translation synergistically extends survival in MYC-driven lymphoma. Cancer Discov (2015).
  5. Quin, J. et al. Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling. Oncotarget (2016).