Poster Presentation 35th Lorne Cancer Conference 2023

Targeting Ribosome Biogenesis using the Inhibitor of RNA Polymerase I Transcription CX-5461 in the Treatment of Multiple Myeloma (#153)

Kezia Gitareja 1 , Kylee H MacLachlan 2 , Jian Kang 1 3 , Andrew Cuddihy 3 , Nadine Hein 4 , Carleen Cullinane 3 , Natalie Brajanovski 3 , Richard B Pearson 3 , Ross D Hannan 4 , Gretchen Poortinga 3 , Simon J Harrison 3 , Elaine Sanij 1 3
  1. St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
  2. Memorial Sloan Kettering Cancer Centre, New York, NY, United States
  3. Research Division, Peter MacCallum Cancer Centre, Parkville, VIC, Australia
  4. The John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia

BACKGROUND: RNA polymerase I (Pol I) transcription of ribosomal RNA genes within the nucleoli is consistently upregulated in cancer. Our laboratory developed CX-5461, a highly selective inhibitor of Pol I transcription [1]. Our preclinical studies demonstrated that single-agent treatment with CX-5461 provides a significant survival benefit in various pre-clinical cancer models [1-3]. Our first-in-human study has also shown a promising anti-tumour activity in three of six heavily pre-treated multiple myeloma (MM) patients, supporting CX-5461 as a promising treatment for MM [4]. However, drug resistance eventually occurs, indicating combination drug therapy is essential.

 

AIM: To examine the efficacy of CX-5461 as a single agent and in combination with other agents having proven clinical or promising preclinical efficacy in MM.

 

METHODS: We measured the effects of CX-5461 in human myeloma cell lines (HMCLs), 5T33 murine myeloma cells and MM patient samples. CX-5461 efficacy was tested in NSG and C57BL/KaLwRij mice transplanted with 5T33 cells. We conducted a high-throughput screen in HMCLs of CX-5461 combined with different agents. The effect of combining CX-5461 with the histone deacetylase inhibitor (HDACi) panobinostat was tested in vivo using Vk*MYC and 5T33-KaLwRij MM murine models.

 

RESULTS: CX-5461 showed anti-proliferative effects and cell death in vitro, with proteomic studies exhibiting enrichment of factors involved in cell cycle control and DNA damage response. There was increased survival benefit in immunocompetent 5T33-KaLwRij model treated with CX-5461, but not in immunodeficient NSG mice. Peripheral blood mononuclear cells from MM patient treated with CX-5461 displayed increased levels of γH2AX and cleaved caspase 3. Panobinostat demonstrated the most impressive synergy with CX-5461. Using both the MYC-driven Vk*MYC model and the non-MYC-driven 5T33-KaLwRij models of MM, we showed that CX-5461 with panobinostat provides a significant survival advantage.

 

CONCLUSION: CX-5461 enhances cell cycle arrest, DNA damage and cell death and exhibits immuno-stimulatory activities in pre-clinical MM models. Combining CX-5461 with panobinostat produces a survival advantage in both the Vk*MYC and the 5T33-KaLwRij models of MM. These results will direct subsequent clinical trials using CX-5461 in combination drug therapy.

 

  1. 1. Bywater MJ, Poortinga G, Sanij E, Hein N, Peck A, Cullinane C et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell 2012; 22: 51-65.
  2. 2. Devlin JR, Hannan KM, Hein N, Cullinane C, Kusnadi E, Ng PY et al. Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma. Cancer Discov 2016; 6: 59-70.
  3. 3. Hein N, Cameron DP, Hannan KM, Nguyen NN, Fong CY, Sornkom J et al. Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population. Blood 2017; 129: 2882-2895.
  4. 4. Khot A, Brajanovski N, Cameron DP, Hein N, Maclachlan KH, Sanij E et al. First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study. Cancer Discov 2019; 9: 1036-1049.