Poster Presentation 30th Lorne Cancer Conference 2018

Novel combination therapies with the RNA polymerase I inhibitor CX-5461 significantly improve efficacy in multiple myeloma (#197)

Kylee Maclachlan 1 2 , Andrew Cuddihy 2 , Nadine Hein 3 , Carleen Cullinane 2 , Simon Harrison 1 , Ross Hannan 1 2 3 4 5 6 , Gretchen Poortinga 1 2 7
  1. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
  2. Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  3. Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
  4. School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia
  5. Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia
  6. Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia
  7. Department of Medicine, St Vincent's Hospital, Melbourne, VIC, Australia

BACKGROUND: rDNA transcription is consistently dysregulated in cancer, with RNA polymerase I (Pol I) hyperactivity providing a survival checkpoint in haematological cancers1.

Our laboratory developed CX-5461, a highly selective small molecule inhibitor of Pol I transcription of ribosomal genes2, currently in early phase clinical trials. CX-5461 induces cell death via a p53-dependent nucleolar surveillance response, and a p53-independent nucleolar-specific DNA damage response (DDR), killing malignant cells while sparing normal cells1,3. CX-5461 increases survival in murine models of B-cell lymphoma, acute myeloid leukaemia and now multiple myeloma (MM)1,3-5. However, resistance eventually develops, indicating combination drug therapy is essential.

AIM: to examine the efficacy of CX-5461 in combination with agents having proven clinical or promising preclinical efficacy in MM.

METHODS: we conducted a boutique, high-throughput screen in myeloma cell lines using CX-5461 combined with a select panel of agents. We measured the effect of CX-5461 on proliferation, cell death, cell cycle distribution, biomarkers of DDR and on-target effects. CX-5461 and the histone deacetylase inhibitor (HDACi) panobinostat were combined in both the tVk*MYC6 model of MM, and in KaLwRij mice transplanted with 5T33 cells.

RESULTS: CX-5461 showed increased anti-proliferative effect and cell death in combination with multiple drug classes. The proteasome inhibitor carfilzomib and the HDACi panobinostat demonstrated the most impressive synergy with CX-5461. In 2 distinct immunocompetent models, CX-5461 with panobinostat provides a significant survival advantage. Prolonged combination dosing in the slower tVk*MYC model gave no increase in haematological toxicity.

We are currently interrogating the molecular synergistic response of this combination, including p53-dependent and –independent responses, and the ATM/ATR signalling pathway. Ongoing work is investigating the efficacy of the triplet drug combination of CX-5461, panobinostat and carfilzomib.

CONCLUSION: CX-5461 shows increased efficacy when combined with multiple drug classes, with panobinostat and carfilzomib showing the most promise in vitro. Combination of CX-5461 with panobinostat increases survival in 2 models of MM. These results will inform subsequent clinical trials utilising combination drug therapy.

  1. 1. Bywater et al., Cancer Cell 2012
  2. 2. Drygin et al., Cancer Research 2011
  3. 3. Quin et al, Oncotarget, 2016
  4. 4. Devlin et al., Cancer Discovery 2016
  5. 5. Hein et al., Blood 2017
  6. 6. Chesi et al., Blood 2012