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Title: Investigating the role of the anti-malarial drug Atovaquone in anti-cancer therapy
Author: Coates, James T.
ISNI:       0000 0004 8507 3769
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2020
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Radiotherapy (XRT) is used in over half of all cancer treatment regimens and can be administered alone or in tandem with chemotherapeutics to improve clinical outcomes. Sub-physiological levels of oxygen (hypoxia) is a feature of many solid tumours and can diminish the effectiveness of anti-cancer treatments. Though its detrimental impact on treatment efficacy was first realised over half a century ago, hypoxia endures as a significant barrier to improving clinical outcomes. Historically, numerous approaches to alleviate or even exploit tumour hypoxia have been explored; however, none are in widespread clinical use today. Most strategies were predicated on therapeutic agents reaching hypoxic areas that are difficult to penetrate, yielding minimal clinical efficacy. Attempting to increase oxygen supply directly via hyperbaric chambers was similarly ineffective. An emerging alternative approach based on modulating cellular demand for oxygen was recently pioneered by our team. We theorised that reducing oxygen consumption of cells that are located in adequately perfused areas and peri-hypoxic regions might increase the concentration of unmetabolised oxygen able to diffuse across a tumour bed and into hypoxic areas. Using a high-throughput small molecule screen, our team previously identified that the FDA-approved, anti-malarial drug Atovaquone (ATQ) reduces oxygen consumption, upregulates glycolysis, and alleviates tumour hypoxia in vivo. As a consequence of the alleviation of hypoxia, ATQ therapy was furthermore shown to synergise with XRT. ATQ is a ubiquinone analogue, suppressing oxidative phosphorylation via direct inhibition of Complex III subunit bc1 of the electron transport chain (ETC). ATQ is a well-studied anti-malarial agent and our team is actively undertaking multiple clinical studies to evaluate its suitability as a clinical hypoxia modifier. This thesis builds on our teams' previous work by exploring the broader effects of ATQ in an anti-cancer setting. The first experimental chapter (Chapter 3) probes the reversibility and tolerability of ATQ in vitro and in vivo before exploring preliminary mechanistic dependencies for how ATQ reverses hypoxia. Metabolic reprogramming towards a more glycolytic phenotype has long been implicated as a key promoter of aggressiveness and metastatic spread and so Chapter 4 probes the effects of ATQ on cancer cell migration in vitro and metastatic potential in vivo. In the last experimental chapter (Chapter 5), we reveal that ATQ potentiates the anti-cancer efficacy of platinum-class chemotherapy agents by modulating ETC-driven oxidative stress. Chapter 6 summarises the findings of the thesis as a whole and discusses future directions. Together, the data presented in this thesis suggests that ATQ is a translationally viable and well-tolerated hypoxia modifying agent having pleotropic effects that are undoubtedly deserving of further study.
Supervisor: McKenna, Gillies ; Higgins, Geoff Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Radiobiology ; Cancer ; Cell Metabolism