Investigation of atovaquone-induced spatial changes in tumour hypoxia assessed by hypoxia PET/CT in non-small cell lung cancer patients

Pauline Bourigault,Michael Skwarski,Ruth E Macpherson,Geoff S Higgins,Daniel R Mcgowan

doi:10.1186/s13550-021-00871-x

Abstract

BackgroundTumour hypoxia promotes an aggressive tumour phenotype and enhances resistance to anticancer treatments. Following the recent observation that the mitochondrial inhibitor atovaquone increases tumour oxygenation in NSCLC, we sought to assess whether atovaquone affects tumour subregions differently depending on their level of hypoxia.MethodsPatients with resectable NSCLC participated in the ATOM trial (NCT02628080). Cohort 1 (n = 15) received atovaquone treatment, whilst cohort 2 (n = 15) did not. Hypoxia-related metrics, including change in mean tumour-to-blood ratio, tumour hypoxic volume, and fraction of hypoxic voxels, were assessed using hypoxia PET imaging. Tumours were divided into four subregions or distance categories: edge, outer, inner, and centre, using MATLAB.ResultsAtovaquone-induced reduction in tumour hypoxia mostly occurred in the inner and outer tumour subregions, and to a lesser extent in the centre subregion. Atovaquone did not seem to act in the edge subregion, which was the only tumour subregion that was non-hypoxic at baseline. Notably, the most intensely hypoxic tumour voxels, and therefore the most radiobiologically resistant areas, were subject to the most pronounced decrease in hypoxia in the different subregions.ConclusionsThis study provides insights into the action of atovaquone in tumour subregions that help to better understand its role as a novel tumour radiosensitiser.Trial registration: ClinicalTrials.gov, NCT0262808. Registered 11th December 2015, https://clinicaltrials.gov/ct2/show/NCT02628080

Highlights

Tumour hypoxia promotes an aggressive tumour phenotype and enhances resistance to anticancer treatments
Changes of to-blood ratio (TBR) in tumour subregions Atovaquone-induced changes in hypoxia were initially assessed in tumours overall and in tumour subregions, using four-hour hypoxia Positron emission tomography (PET)-CT
Following the recent demonstration that the mitochondrial inhibitor atovaquone decreases tumour hypoxia in patients with Non-small cell lung cancer (NSCLC), this study shows that the reduction in TBR and hypoxic volume (HV) occurred in the outer, inner, and centre tumour subregions

Summary

Introduction

Tumour hypoxia promotes an aggressive tumour phenotype and enhances resistance to anticancer treatments. Following the recent observation that the mitochondrial inhibitor atovaquone increases tumour oxygenation in NSCLC, we sought to assess whether atovaquone affects tumour subregions differently depending on their level of hypoxia. Coupled with the high metabolic requirements of many tumours, this leads to an imbalance in oxygen supply and demand and so causes tumour hypoxia. Various pre-clinical and clinical studies have highlighted that tumour hypoxia enhances resistance to anticancer treatments, RT, and promotes an aggressive tumour phenotype [6]. Hypoxia is closely associated with several ‘hallmarks of cancer’ such as reprogramming energy metabolism, inducing angiogenesis, and resisting cell death [8]. Gray and colleagues suggested for the first time in the 1950s that hypoxia could influence radiotherapy outcomes as the radioresistance of hypoxic tumour cells increases by a factor of up to three compared to normoxic tumour cells [5, 9, 10]

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