Poster Presentation 36th Lorne Cancer Conference 2024

Targeting the nucleoli as a strategy to treat ovarian cancer (#210)

Shalini Sundramurthi Chelliah 1 2 , Jiachen Xuan 3 , Ruofei Liu 1 , Henry Beetham 3 4 , Rick Pearson 2 3 , Kaylene Simpson 3 4 , Jian Kang 1 , Elaine Sanij 1 2 3 5
  1. St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
  2. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
  3. Research Division, Peter MacCallum Cancer Centre, Parkville, VIC, Australia
  4. Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  5. Department of Medicine- St Vincent’s Hospital, University of Melbourne, Melbourne, VIC, Australia

The nucleolus is the site of RNA polymerase I (Pol) transcription of ribosomal RNA (rRNA) genes and ribosome subunits assembly. Cancer cells exhibit enlarged nucleoli and hyperactivation of ribosome biogenesis to meet the high demand for protein synthesis. Defects in Pol I transcription and ribosome biogenesis, known as nucleolar stress, disrupt nucleolar morphology and function leading to cell cycle arrest and cell death. The response to nucleolar stress is complex, involving the activation of multiple stress signalling pathways that are yet to be fully understood.

Targeting the nucleoli has emerged as an innovative approach to cancer therapy. CX-5461 (Pidnarulex), a first-in-class selective inhibitor of Pol I transcription has demonstrated therapeutic benefits in various preclinical cancer models [1-5] and in Phase I clinical trials [6,7]. Our work has shown that CX-5461 activates nucleolar stress and the DNA Damage response (DDR) at the rRNA genes within the nucleoli leading to cell cycle arrestand cell death in ovarian cancer models [5]. Furthermore, CX-5461 exhibits a unique sensitivity profile compared to chemotherapeutics in patient-derived ovarian cancer cell models [5,8]. The encouraging outcomes from a Phase I trial, resulted in CX-5461 receiving a fast-track designation by the FDA for a subset of patients with chemo-resistant ovarian and breast cancers [6].

We propose that CX-5461 represents the first drug in a new class of cancer therapeutics targeting the nucleoli.To identify novel nucleolar stress pathways, we have conducted an arrayed whole-genome CRISPR-Cas9 screen to identify genes whose deletion causes changes in nucleolar morphology. We have identified five types of distinct changes to nucleolar morphology that are linked to inhibition of biological processes including ribosome biogenesis, cell cycle and RNA metabolic processes. Our data highlights the tight coordination between these processes and nucleolar fidelity and identifies specific pathways/ factors that could act as mediators of nucleolar stress and potential therapeutic targets. To complement this screen, we have initiated a drug screen to identify compounds that target the nucleoli, triggering nucleolar stress and growth inhibition of ovarian cancer cells. In summary, our work uncovers novel nucleolar stress pathways that can be harnessed to halt cancer cell growth.

 

 

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