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Modelling the Effects and Responses of DNA Damage Response Inhibitor Drugs / KIRA PUGH

Swansea University Author: KIRA PUGH

  • E-Thesis under embargo until: 29th August 2025

DOI (Published version): 10.23889/SUThesis.68206

Abstract

The increasing complexity of clinical and biological effects of multimodality thera-pies often results in substantial challenges to the clinical and preclinical development of novel therapeutic drugs. Mathematical modelling that is informed by experimen-tal data can aid in understanding and studying...

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Published: Swansea University, Wales, UK 2024
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
Supervisor: Powathil, G.
URI: https://cronfa.swan.ac.uk/Record/cronfa68206
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first_indexed 2024-11-07T11:06:22Z
last_indexed 2024-11-07T11:06:22Z
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spelling v2 68206 2024-11-07 Modelling the Effects and Responses of DNA Damage Response Inhibitor Drugs 3ea2bd043397e68c5eb4d337afcc4a4a KIRA PUGH KIRA PUGH true false 2024-11-07 The increasing complexity of clinical and biological effects of multimodality thera-pies often results in substantial challenges to the clinical and preclinical development of novel therapeutic drugs. Mathematical modelling that is informed by experimen-tal data can aid in understanding and studying the multiple (nonlinear) therapeutic effects and responses of these drugs, which can assist in the preclinical design and development, and its clinical implementation. The multiscale complexity of cancer necessitates the adoption of a multiscale approach, incorporating appropriate mechanisms to obtain meaningful and predictive mathematical models to study the therapeutic effects and outcomes.DNA damage occurs thousands of times per cell per day. The DNA damage response (DDR) is responsible for detecting and repairing DNA damage. The DDR pathways can be exploited for anti-cancer treatments. DDR inhibitor drugs can be used to cause certain pathways to stop working, which enhances cancer growth inhibition and/or death. The ataxia-telangiectasia and Rad3-related (ATR) inhibitor ceralasertib and the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib have shown synergistic activity, in vitro, in the FaDu ATM-KO cell line. Experimental data has shown that when combined, lower doses of the drugs for shorter treatment times can induce greater toxicity in cancer cells compared to using either drug as a monotherapy.Here, we develop biologically-motivated mathematical models that include the cell cycle-specific interactions of both ceralasertib and olaparib to: (1) explore the prominence of each cell cycle-specific drug interaction, (2) find optimal doses of ceralasertib and olaparib in combination, and (3) study the competition for space between drug-sensitive and drug-resistant cancer cells that are subjected to DDR inhibitor drugs. These models are implemented using both deterministic ordinary differential equation (ODE) models and a stochastic agent-based model (ABM) and are parameterised and evaluated against in vitro data. E-Thesis Swansea University, Wales, UK Mathematical modelling, cell cycle, DDR inhibitor drugs 29 8 2024 2024-08-29 10.23889/SUThesis.68206 A selection of content is redacted or is partially redacted from this thesis to protect sensitive and personal information. COLLEGE NANME COLLEGE CODE Swansea University Powathil, G. Doctoral Ph.D EPSRC EPSRC 2024-11-07T11:16:03.1530893 2024-11-07T10:59:47.8090227 Faculty of Science and Engineering School of Mathematics and Computer Science - Mathematics KIRA PUGH 1 Under embargo Under embargo 2024-11-07T11:04:38.0373093 Output 64220672 application/pdf E-Thesis true 2025-08-29T00:00:00.0000000 Copyright, The Author, Kira Pugh, 2024 CC BY-ND - Distributed under the terms of a Creative Commons Attribution-NoDerivatives 4.0 International License (CC BY-ND 4.0). true eng https://creativecommons.org/licenses/by-nd/4.0/
title Modelling the Effects and Responses of DNA Damage Response Inhibitor Drugs
spellingShingle Modelling the Effects and Responses of DNA Damage Response Inhibitor Drugs
KIRA PUGH
title_short Modelling the Effects and Responses of DNA Damage Response Inhibitor Drugs
title_full Modelling the Effects and Responses of DNA Damage Response Inhibitor Drugs
title_fullStr Modelling the Effects and Responses of DNA Damage Response Inhibitor Drugs
title_full_unstemmed Modelling the Effects and Responses of DNA Damage Response Inhibitor Drugs
title_sort Modelling the Effects and Responses of DNA Damage Response Inhibitor Drugs
author_id_str_mv 3ea2bd043397e68c5eb4d337afcc4a4a
author_id_fullname_str_mv 3ea2bd043397e68c5eb4d337afcc4a4a_***_KIRA PUGH
author KIRA PUGH
author2 KIRA PUGH
format E-Thesis
publishDate 2024
institution Swansea University
doi_str_mv 10.23889/SUThesis.68206
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Mathematics and Computer Science - Mathematics{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Mathematics and Computer Science - Mathematics
document_store_str 0
active_str 0
description The increasing complexity of clinical and biological effects of multimodality thera-pies often results in substantial challenges to the clinical and preclinical development of novel therapeutic drugs. Mathematical modelling that is informed by experimen-tal data can aid in understanding and studying the multiple (nonlinear) therapeutic effects and responses of these drugs, which can assist in the preclinical design and development, and its clinical implementation. The multiscale complexity of cancer necessitates the adoption of a multiscale approach, incorporating appropriate mechanisms to obtain meaningful and predictive mathematical models to study the therapeutic effects and outcomes.DNA damage occurs thousands of times per cell per day. The DNA damage response (DDR) is responsible for detecting and repairing DNA damage. The DDR pathways can be exploited for anti-cancer treatments. DDR inhibitor drugs can be used to cause certain pathways to stop working, which enhances cancer growth inhibition and/or death. The ataxia-telangiectasia and Rad3-related (ATR) inhibitor ceralasertib and the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib have shown synergistic activity, in vitro, in the FaDu ATM-KO cell line. Experimental data has shown that when combined, lower doses of the drugs for shorter treatment times can induce greater toxicity in cancer cells compared to using either drug as a monotherapy.Here, we develop biologically-motivated mathematical models that include the cell cycle-specific interactions of both ceralasertib and olaparib to: (1) explore the prominence of each cell cycle-specific drug interaction, (2) find optimal doses of ceralasertib and olaparib in combination, and (3) study the competition for space between drug-sensitive and drug-resistant cancer cells that are subjected to DDR inhibitor drugs. These models are implemented using both deterministic ordinary differential equation (ODE) models and a stochastic agent-based model (ABM) and are parameterised and evaluated against in vitro data.
published_date 2024-08-29T11:16:01Z
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score 11.037603

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