E-Thesis 2 views
Modelling the Effects and Responses of DNA Damage Response Inhibitor Drugs / KIRA PUGH
Swansea University Author: KIRA PUGH
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...
| Published: |
Swansea University, Wales, UK
2024
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| 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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| 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 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. |
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| Item Description: |
A selection of content is redacted or is partially redacted from this thesis to protect sensitive and personal information. |
| Keywords: |
Mathematical modelling, cell cycle, DDR inhibitor drugs |
| College: |
Faculty of Science and Engineering |
| Funders: |
EPSRC |