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High-Grade Serous Ovarian Cancer Drug Development: Investigating the mechanism of action of PLK1 and BRD4 inhibitors in HGSOC / Agne Pociute

Swansea University Author: Agne Pociute

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Abstract

Background. In females, ovarian cancer is the 5th cancer-related death cause and the deadliest gynaecological cancer. High-grade serous ovarian cancer accounts for the majority of ovarian cancer cases and is associated with poor prognosis and high rates of resistance. Although, the majority of new t...

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Published: Swansea, Wales, UK 2024
Institution: Swansea University
Degree level: Master of Research
Degree name: MSc by Research
Supervisor: Francis, Lewis ; Gonzalez, Deya
URI: https://cronfa.swan.ac.uk/Record/cronfa66313
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Abstract: Background. In females, ovarian cancer is the 5th cancer-related death cause and the deadliest gynaecological cancer. High-grade serous ovarian cancer accounts for the majority of ovarian cancer cases and is associated with poor prognosis and high rates of resistance. Although, the majority of new therapeutics show success in preclinical stages they do not provide significant benefits in clinical settings. New treatment strategies relating to cancer hallmarks such as sustained proliferative signalling and non-mutational epigenetic modifications which are regulated through proteins such as polo-like kinase 1, PLK1, and bromodomain-containing protein, BRD4, respectively, hold potential. Results. An advanced pre-clinical drug development pipeline was developed, incorporating RNA and ATAC-seq, to identify the mechanism of action of BI 2536 and BI 6727, two compounds that target PLK1 in isolation and/or in combination with BRD4. High-grade ovarian cell lines expressed PLK1 and BRD4 and higher PLK1 expression was associated with greater sensitivity to BI 2536 and BI 6727. Drugs reduced cell viability through induction of G2/M cell cycle arrest, followed by DNA damage and apoptosis. RNA-seq and ATAC-seq results provide evidence for the inhibition of PLK1 function as cell cycle pathways were differentially regulated whereas BRD4 expression and genes were not affected significantly. Impact. Implementation of functional genomics, involving genomics, transcriptomics, and epigenomics, into drug development and screening, was proven to be a robust strategy to study cancer complexity and result in new druggable target discoveries. Both compounds have undergone clinical trials, with inconsistent classification and an in-depth understanding of their mechanism of action in HGSOC could inform future PLK1 targeting strategies for HGSOC.
Keywords: Ovarian cancer, drug development, PLK1, BRD4, BI 2536, BI 6727, ATAC-seq, RNA-seq
College: Faculty of Medicine, Health and Life Sciences