Invited Speaker Presentation 29th Lorne Cancer Conference 2017

Targeting the ribosome as a strategy to treat cancer (#37)

Rick Pearson 1 2 , Jennifer R Devlin 1 , Richard J Rebello 3 , Katherine M Hannan 4 , Elaine Sanij 1 , Shunfei Yan 1 , Keefe Chan 1 , Jessica Ahern 1 , Jinbae Son 1 , Carleen Cullinane 1 , Luc Furic 1 3 , Karen E Sheppard 1 , Ross D Hannan 1 2 4 , Richard Pearson 1 2
  1. Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
  3. Department of Anatomy & Developmental Biology, Monash University, Melbourne, Victoria, Australia
  4. Department of Cancer Biology and Therapeutics, John Curtain School of Medical Research, 2601, ACT, Australia

Malignancies including haematological, prostate and ovarian cancers (OVCAs) are characterized by deregulated signaling through the PI3K/RAS/MYC network and are associated with elevated rates of ribosome biogenesis and mTORC1/eIF4E-driven protein synthesis suggesting they may be vulnerable to therapeutic strategies that target the ribosome. Here we investigate the therapeutic efficacy of targeting multiple nodes of the network controlling the ribosome. We utilized mouse models of MYC-driven lymphoma (Eμ-Myc) and prostate cancer (HI-MYC) as well as an extensive panel of OVCA cell lines. Simultaneous inhibition of ribosomal RNA synthesis and repression of protein translation was achieved by treating mice with the novel RNA polymerase I inhibitor CX-5461 and PI3K/AKT/mTORC1 and PIM kinase 1 signaling inhibitors alone and in combination. Furthermore, we performed pharmaco-genomic analysis of the response of OVCA to CX-5461 to identify additional pathways that can be targeted to increase the efficacy of targeting ribosome biogenesis in OVCA.

Combined inhibition of ribosome biogenesis and function significantly improved therapeutic outcomes in lymphoma and prostate cancer models. CX-5461 and Everolimus (mTORC1 inhibitor) co-treatment more than doubled the survival of Eμ-Myc lymphoma-bearing mice. While both classes of inhibitor suppress rDNA transcription, they treat MYC-driven malignancy through distinct molecular mechanisms facilitating their combinatorial effects1. PIM kinase has been shown to regulate eIF4E-driven protein synthesis in prostate cancer cell lines. Co–treatment of HI-MYC mice with CX-5461 and the PIM kinase inhibitor CX-6258 reverted highly invasive disease to low-grade prostate intraepithelial neoplasia and inhibited the growth of a patient derived xenograft from an aggressive, metastatic prostate tumour2. Pharmaco-genomic analysis of the response of OVCA to CX-5461 revealed that sensitivity to CX-5461 correlates with a DNA damage gene signature. Combining CX-5461 with inhibitors of the ATM and ATR kinases as well as PARP demonstrated synergistic killing of OVCA cells in vitro and in vivo.

These findings demonstrate that combining inhibition or ribosome biogenesis alone and in combination with standard and targeted therapies that are in clinical trials provides an effective new therapeutic approach to treat the high proportion of cancers characterized by dysregulation of the PI3K/RAS/MYC network.

  1. 1. Devlin et al Cancer Discovery (2016);6(1):59-70. 2. Rebello et al Clinical Cancer Research (2016) 22(22); 5539–52.