Poster Presentation 27th Lorne Cancer Conference 2015

New approach to AML therapy: Inhibition of rDNA transcription by CX-5461 (#269)

Jirawas Sornkom 1 , Nadine Hein 2 , Mark Dawson 1 2 , Gretchen Poortinga 3 , Ross Hannan 1 2 4 5 6
  1. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
  2. Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
  3. Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia
  4. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
  5. Division of Cancer medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
  6. School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia

Recent findings from our group using a novel selective inhibitor of rDNA transcription by polymerase I (Pol I), CX-5461, demonstrate that, haematological malignancies show profound sensitivity to Pol I inhibition. This led us to establish a first-in-class, phase I clinical trial of CX-5461 in patients with lymphoma and leukaemia1-5 at the Peter MacCallum Cancer Centre. In conjunction with the trial, we now aim to advance our understanding of therapeutic Pol I transcription therapy by addressing its efficacy in acute myeloid leukaemia (AML), a refractory disease which is associated with low survival, high risk of relapse and resistance to standard therapy.

To determine the efficacy of CX-5461 in AML, a panel of AML cell lines were treated with CX-5461 and assessed for cell viability. We treated a panel of 30 AML cell lines representing the most common driver mutations found in human AML malignancies. Interestingly, while all lines responded to inhibition of Pol I transcription similarly and demonstrated nucleolar disruption, their response in terms of cell death was variable ranging form IC50 of 48nM through to over 10μM. Surprisingly, although our previous work in lymphomas has demonstrated that p53 plays a central role in the sensitisation of lymphoma cells to CX-54616, in AML, we found that p53 status is not the only factors dictating the sensitivity (Hein and Hannan, unpublished data). These studies indicate that targeting rDNA transcription by CX-5461 may provide a new therapeutic option for treating highly refractory AML in a broad spectrum of patients. We will present this work along with our current update on combination studies using CX-5461 and an emerging bromodomain and extra terminal domain (BET) inhibitor, iBET-151, which has shown impressive efficacy in AML therapy7.    

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  2. Drygin, D. et al. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. Cancer Research 71, 1418–1430 (2011).
  3. Hannan, R. D., Drygin, D. & Pearson, R. B. Targeting RNA polymerase I transcription and the nucleolus for cancer therapy. Expert Opin. Ther. Targets 17, 873–878 (2013).
  4. Hein, N., Hannan, K. M., George, A. J., Sanij, E. & Hannan, R. D. The nucleolus: an emerging target for cancer therapy. Trends Mol Med 19, 643–654 (2013).
  5. Poortinga, G., Quinn, L. M. & Hannan, R. D. Targeting RNA polymerase I to treat MYC-driven cancer. Oncogene (2014).
  6. 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).
  7. Dawson, M. A. et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478, 529–533 (2011).