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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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spelling v2 66313 2024-05-06 High-Grade Serous Ovarian Cancer Drug Development: Investigating the mechanism of action of PLK1 and BRD4 inhibitors in HGSOC a972704e13fc32290a45167daef67d45 Agne Pociute Agne Pociute true false 2024-05-06 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. E-Thesis Swansea, Wales, UK Ovarian cancer, drug development, PLK1, BRD4, BI 2536, BI 6727, ATAC-seq, RNA-seq 1 5 2024 2024-05-01 COLLEGE NANME COLLEGE CODE Swansea University Francis, Lewis ; Gonzalez, Deya Master of Research MSc by Research 2024-05-06T17:33:06.8837435 2024-05-06T17:18:11.2905504 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Agne Pociute 1 66313__30296__490e90e7b6414f2bbcbe7785d1ad6684.pdf Pociute_Baseviciene_Agne_MSc_Research_Thesis_Final_Redacted_Signature.pdf 2024-05-06T17:29:22.2543066 Output 4353541 application/pdf E-Thesis – open access true Copyright: The Author, Agne (Pociute) Baseviciene, 2024. true eng
title High-Grade Serous Ovarian Cancer Drug Development: Investigating the mechanism of action of PLK1 and BRD4 inhibitors in HGSOC
spellingShingle High-Grade Serous Ovarian Cancer Drug Development: Investigating the mechanism of action of PLK1 and BRD4 inhibitors in HGSOC
Agne Pociute
title_short High-Grade Serous Ovarian Cancer Drug Development: Investigating the mechanism of action of PLK1 and BRD4 inhibitors in HGSOC
title_full High-Grade Serous Ovarian Cancer Drug Development: Investigating the mechanism of action of PLK1 and BRD4 inhibitors in HGSOC
title_fullStr High-Grade Serous Ovarian Cancer Drug Development: Investigating the mechanism of action of PLK1 and BRD4 inhibitors in HGSOC
title_full_unstemmed High-Grade Serous Ovarian Cancer Drug Development: Investigating the mechanism of action of PLK1 and BRD4 inhibitors in HGSOC
title_sort High-Grade Serous Ovarian Cancer Drug Development: Investigating the mechanism of action of PLK1 and BRD4 inhibitors in HGSOC
author_id_str_mv a972704e13fc32290a45167daef67d45
author_id_fullname_str_mv a972704e13fc32290a45167daef67d45_***_Agne Pociute
author Agne Pociute
author2 Agne Pociute
format E-Thesis
publishDate 2024
institution Swansea University
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
active_str 0
description 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.
published_date 2024-05-01T17:33:05Z
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score 11.037603

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