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Targeting the nucleoli in cancer therapy

Hosted by: Professor Leonie Quinn

Abstract

The nucleoli are subdomains of the nucleus that form around actively transcribed ribosomal RNA (rRNA) genes. The highly repetitive and transcribed nature of the rRNA genes (rDNA) by RNA polymerase I (Pol I) poses a challenge for DNA repair and replication machineries. Using a CRISPR-Cas9 screening approach, we uncover surveillance networks within the nucleolus that respond to rDNA damage and form part of the nucleolar stress response.

Targeting Pol I transcription with the first-in-class drug CX-5461 induces potent nucleolar stress response and has demonstrated therapeutic efficacy in various preclinical cancer models and in phase I clinical trials. To identify novel nucleolar stress pathways, we conducted an arrayed whole-genome CRISPR-Cas9 screen to identify genes whose deletion causes changes in nucleolar morphology as an indicator of nucleolar stress. Moreover, we completed a high-throughput drug screen of 23,000 compounds to identify compounds that trigger nucleolar stress and inhibit ovarian cancer cell growth. In summary, our work uncover specific pathways/factors as mediators of nucleolar stress and potential cancer therapeutic targets.

Biography

Associate Professor Elaine Sanij is a cancer biologist, a Laboratory Head at St Vincent’s Institute of Medical Research (SVI) and a theme leader at the Barrie Dalgleish Research Centre for Myeloma and Related Blood Cancers, a partnership between 6 organisations within the Parkville precinct in Melbourne.

A/Prof Sanij’s research is focused on developing innovative cancer therapeutics targeting the nucleoli and ribosome biogenesis. She received her PhD from Monash University (2003), a Cancer Research UK fellowship (2003-2006) and was a Senior Research Fellow at the Peter MacCallum Cancer Centre (2006- 2021). She currently holds prestigious funding awards from the NHMRC, MRFF, Cancer Australia and the US Department of Defense.