Poster Presentation 28th Lorne Cancer Conference 2016

Novel combination therapies targeting both RNA Polymerase I and Polymerase II transcription show synergistic efficacy in MLL-rearranged and core binding factor acute myeloid leukaemia  (#256)

Jirawas Sornkom 1 , Nadine Hein 1 2 , Chun Yew Fong 1 , Mark Dawson 1 , Carleen Cullinane 1 , Sean O'Brien 3 , Gretchen Poortinga 1 4 , Ross Hannan 1 2 5 6 7
  1. Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. ACRF Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, Canberra, ACT, Australia
  3. Senhwa Biosciences, San Diego, CA, USA
  4. Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia
  5. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
  6. Division of Cancer medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
  7. School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia

Acute myeloid leukaemia (AML), arising from myeloid progenitors, is one of the most aggressive and refractory leukaemias. Recent advances in the understanding of AML pathogenesis have highlighted the importance of transcription dysregulation and its central role in AML leukaemogenesis. Here we present our ongoing investigation of a highly effective, non-cytotoxic therapeutic strategy, using two classes of emerging small molecule therapies targeting transcription machineries.

CX-5461 is a novel inhibitor of RNA polymerase I (Pol I) mediated rDNA transcription. CX-5461 treatment resulted in significant tumour regression in transgenic MLL-rearranged (MLL-r) AML and AML xenograft models. Representing the emerging class of drugs targeting chromatin regulation, IBET-151 (GSK) is an inhibitor of BET proteins, epigenetic readers known to be positive regulators of RNA polymerase II (Pol II) transcription. IBET-151 has shown clinical promise against certain AML subtypes, including the aggressive MLL-r AML. Despite encouraging outcomes, it is evident that either CX-5461 or IBET-151 as single agents are unlikely to overcome AML heterogeneity in the long-term. Thus, we predict that rational combination targeting of these two major transcriptional programs will further improve their efficacy. Indeed, in vitro studies assaying the combined treatment of CX-5461 and IBET-151 in AML cell lines demonstrated a lethal synergistic effect in MLL-r cell lines after 48hr. Extending the co-treatment period to 6 days further demonstrated a synergistic anti-proliferative effect in MLL-r AML (MV4-11) and a non-MLL-r, CBF mutated line (Kasumi-1).

To determine if this synergy is efficacious in vivo, we treated a transgenic model of MLL-AF9; NrasG12D with CX-5461 and IBET-151. Dosing at the established MTD, these agents significantly extended overall survival of MLL-AF9; NrasG12D mice compared to single drug treatment. We will discuss potential mechanisms supporting the observed synergy, including the impact on the MYC oncogene, global effects on transcriptional programs and the subsequent activation of critical cancer cell checkpoints. 

  1. Cancer Genome Atlas Research Network. (2013). Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. The New England Journal of Medicine, 368(22), 2059–2074.
  2. Bywater, M. J., Poortinga, G., Sanij, E., Hein, N., Peck, A., Cullinane, C., et al. (2012). Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell, 22(1), 51–65.
  3. Dawson M., Prinjha R., Dittmann A., Giotopoulos G., Bantscheff M., Chan W., et al. (2011) Inhibition of bet recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478: 529–533.
  4. Zuber, J., Radtke, I., Pardee, T. S., Zhao, Z., Rappaport, A. R., Luo, W., et al. (2009). Mouse models of human AML accurately predict chemotherapy response. Genes & Development, 23(7), 877–889.