New Approach to AML Therapy: Inhibition of rDNA Transcription by CX-5461 — ASN Events
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  3. New Approach to AML Therapy: Inhibition of rDNA Transcription by CX-5461

New Approach to AML Therapy: Inhibition of rDNA Transcription by CX-5461 (#150)

Jirawas Sornkom 1 , Nadine Hein 1 , Mark Dawson 1 , Sean O'brien 2 , Denis Drygin 2 , Gretchen Poortinga 1 , Ross Hannan 1
  1. Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Senhwa Biosciences, San Diego, CA, USA

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 leukaemia1-6 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.

We have shown in a genetically engineered mouse model of aggressive AML that inhibition of Pol I transcription by CX-5461 has high efficacy as single agent and outperformed the standard therapies (Hein and Hannan, unpublished data). Furthermore, we have assayed a panel of 30 AML cells lines representing the most common driver mutations found in human AML malignancies for sensitivity to CX-5461. Interestingly, while all cells show decreased rRNA transcription and nucleolar disruption upon CX-5461 treatment, indicating that CX-5461 is on-target, this panel of AML lines demonstrate a broad range of sensitivity via apoptotic cell death to Pol I therapy. We are currently utilising multiple approaches to identify what factors might play roles in conferring the sensitivity of AML to CX-5461.

In parallel, to improve the therapeutic efficacy to overcome both intrinsic and acquired resistance to CX-5461 and to extend patient survival in clinic, we are also studying the therapeutic efficacy of CX-5461 in combination with other emerging therapies know to have efficacy against AML, such as BRD4 inhibitors, HDAC inhibitors, CDK9 inhibitors etc. To date, we have uncovered synergistic effects on cell death when CX-5461 is used in combination with either a BRD4 inhibitor (iBET-151)7 or CDK1/2/5/9 inhibitor (Dinaciclib), specifically in AML lines with MLL translocations.    

  1. Bywater, M. J., Pearson, R. B., McArthur, G. A. & Hannan, R. D. Dysregulation of the basal RNA polymerase transcription apparatus in cancer. Nat. Rev. Cancer 13, 299–314 (2013)
  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). doi:10.1038/onc.2014.13
  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).