An investigation into the effect of atovaquone on clinical parameters of tumour hypoxia: a window of opportunity study in patients with non-small cell lung carcinoma

In no other tumour type is the need to improve tumour radiation response more evident than in non-small cell lung cancer (NSCLC), where exceptionally poor radiotherapy outcomes are part of everyday clinical practice. As tumour hypoxia confers profound resistance to radiation, there is significant interest in developing novel hypoxia modifiers as radiosensitisers.
Previous attempts to address tumour hypoxia have largely focused on improving tumour oxygen supply. However, despite decades of clinical trials combining promising agents with radiotherapy, no hypoxia modifiers are in widespread clinical use. The reasons for this include an absence of clinical studies confirming hypoxia modulation and a lack of validated methods to evaluate tumour hypoxia in order to select patients for treatment.
An entirely new strategy to tackle hypoxia is to reduce tumour oxygen consumption through inhibition of oxidative phosphorylation. Recently, the commonly prescribed antimalarial drug atovaquone has been discovered as the most promising agent for this purpose. The translational research presented in this thesis represents a carefully measured approach in developing atovaquone as a clinical radiosensitiser. The first aim of this work was to design and conduct a clinical trial to confirm that atovaquone reduces tumour hypoxia in patients. The Atovaquone as a Tumour hypOxia Modifier (ATOM) trial was a ‘window of opportunity’ study in patients with resectable NSCLC and used a multitude of methods to investigate the effect of atovaquone on tumour hypoxia. These included hypoxia PET imaging with FMISO and FAZA PET-CT, perfusion CT and measurement of the endogenous plasma hypoxia markers VEGF, CAIX, OPN and miR-210. Following tumour resection, extensive tumour immunohistochemical analysis was also conducted for CAIX and for exogenous pimonidazole. In recognition of the importance of developing clinical hypoxia biomarkers, the second aim of this work was to assess the validity of the techniques used by performing correlative analysis of the numerous endpoints of this study.
An exciting finding from this work was that atovaquone treatment rapidly reduced tumour hypoxia in the vast majority of patients, as measured by hypoxia PET imaging. This represents the first clinical confirmation of proof of principle not only for atovaquone as a hypoxia modifier, but also for this new approach in tackling tumour hypoxia by reducing oxygen consumption.
Regarding the evaluation of hypoxia biomarkers, a lack of agreement was generally observed between endogenous hypoxia markers, as well as between such markers and hypoxia PET imaging. This highlights the well-recognised challenge of evaluating tumour hypoxia using surrogate measures. However, correlation between plasma miR-210 expression and hypoxia PET imaging was observed, thus providing provisional support that this recently discovered circulating marker may hold more promise as a clinical hypoxia biomarker in NSCLC.
Given the convincing reduction in tumour hypoxia observed following atovaquone treatment in this study, a new clinical trial has been developed which will combine this agent with chemoradiotherapy in patients with NSCLC.

Advisor: Higgins, G