Hill, Roger (2019) Optimising chronotherapy for gastrointestinal cancers. PhD thesis, University of Warwick.

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Abstract

Gastrointestinal cancers are some of the most common and deadly cancers in the world. The improvement of current treatments is of great importance to improve patients survival and quality of life and decrease the burden of these cancers. Within this thesis we will focus on two particular cancers: colorectal and pancreatic cancer, and their treatment by three cytotoxics oxaliplatin, 5-fluorouracil and irinotecan. The improvement of treatment will focus on the use of circadian rhythms. Circadian rhythms are the innate approximately 24 hour rhythms present in almost all living organisms. Treatments which take this innate rhythm into account is known as chronotherapy and has already been shown to improve patient outcomes. However, recent findings highlight the need of personalising drug timing to account for the patient’s gender, chronotype and genetic background. We will firstly look at potential improvements which can be made directly to current treatment protocols by using mathematical models. A model of the drug solution dynamics from an infusion pump to the patient blood will be developed and used to improve the accuracy of chronomodulated drug delivery. Subsequently, semi-mechanistic models of individual patient drug pharmacokinetics will be connected to the pump-to-patient model and used as a method of patient stratification in order to better personalise treatments. We will then use a multiscale approach- from in vitro to mouse studies- to build a physiologically-based whole body model of oxaliplatin pharamcokinetics to look at sexual dimorphism in the drug chronoefficacy and chronotoxicity. This model can then be used to connect differences in drug dynamics to measurable biomarkers and help inform future human trials. Overall, this thesis aims to develop mathematical tools to personalize chronotherapy treatments and further the knowledge available to biologists and clinicians working in this important area of cancer research.

Item Type:	Thesis (PhD)
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RM Therapeutics. Pharmacology
Library of Congress Subject Headings (LCSH):	Gastrointestinal system -- Cancer, Circadian rhythms, Chronopharmacology
Official Date:	October 2019
Dates:	Date Event October 2019 UNSPECIFIED
Institution:	University of Warwick
Theses Department:	Centre for Complexity Science
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Ballesta, Annabelle
Format of File:	pdf
Extent:	xvi, 143 leaves : illustrations, charts
Language:	eng

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