Mitochondrial inhibitor atovaquone increases tumor oxygenation and inhibits hypoxic gene expression in patients with non-small cell lung cancer
Authors
Skwarski, M.McGowan, D. R.
Belcher, E.
Di Chiara, F.
Stavroulias, D.
McCole, M. G.
Derham, J.
Chu, K. Y.
Teoh, E.
Chauhan, J.
O'Reilly, D.
Harris, B. H. L.
Macklin, P. S.
Bull, J. A.
Green, M.
Rodriguez-Berriguete, G.
Prevo, R.
Folkes, L. K.
Campo, L.
Ferencz, P.
Croal, P.
Flight, H.
Qi, C.
Holmes, J.
O'Connor, James P B
Gleeson, F.
McKenna, W. G.
Harris, A. L.
Bulte, D.
Buffa, F. M.
Macpherson, R. E.
Higgins, G. S.
Affiliation
Department of Oncology, University of OxfordIssue Date
2021
Metadata
Show full item recordAbstract
Purpose: Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known mitochondrial inhibitor, reduces hypoxia in non-small cell lung cancer (NSCLC). Patients and methods: Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: cohort 1 received oral atovaquone at the standard clinical dose of 750 mg twice daily, while cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Intercohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was perf0rmed. Results: Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction, with median change -28% [95% confidence interval (CI), -58.2 to -4.4]. In contrast, median change in untreated patients was +15.5% (95% CI, -6.5 to 35.5). Linear regression estimated the expected mean HV was 55% (95% CI, 24%-74%) lower in cohort 1 compared with cohort 2 (P = 0.004), adjusting for cohort, tumor volume, and baseline HV. A key pharmacodynamics endpoint was reduction in hypoxia-regulated genes, which were significantly downregulated in atovaquone-treated tumors. Data from multiple additional measures of tumor hypoxia and perfusion are presented. No atovaquone-related adverse events were reported. Conclusions: This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant antitumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC.Citation
Skwarski M, McGowan DR, Belcher E, Di Chiara F, Stavroulias D, McCole M, et al. Mitochondrial Inhibitor Atovaquone Increases Tumor Oxygenation and Inhibits Hypoxic Gene Expression in Patients with Non-Small Cell Lung Cancer. Clin Cancer Res. 2021.Journal
Clinical Cancer ResearchDOI
10.1158/1078-0432.Ccr-20-4128PubMed ID
33597271Additional Links
https://dx.doi.org/10.1158/1078-0432.Ccr-20-4128Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1158/1078-0432.Ccr-20-4128
Scopus Count
Collections
Related articles
- Timing of hypoxia PET/CT imaging after 18F-fluoromisonidazole injection in non-small cell lung cancer patients.
- Authors: Bourigault P, Skwarski M, Macpherson RE, Higgins GS, McGowan DR
- Issue date: 2022 Dec 16
- Combined Oxygen-Enhanced MRI and Perfusion Imaging Detect Hypoxia Modification from Banoxantrone and Atovaquone and Track Their Differential Mechanisms of Action.
- Authors: O'Connor JPB, Tessyman V, Little RA, Babur M, Forster D, Latif A, Cheung S, Lipowska-Bhalla G, Higgins GS, Asselin MC, Parker GJM, Williams KJ
- Issue date: 2024 Oct 1
- Buparlisib with thoracic radiotherapy and its effect on tumour hypoxia: A phase I study in patients with advanced non-small cell lung carcinoma.
- Authors: McGowan DR, Skwarski M, Bradley KM, Campo L, Fenwick JD, Gleeson FV, Green M, Horne A, Maughan TS, McCole MG, Mohammed S, Muschel RJ, Ng SM, Panakis N, Prevo R, Strauss VY, Stuart R, Tacconi EMC, Vallis KA, McKenna WG, Macpherson RE, Higgins GS
- Issue date: 2019 May
- Preclinical evidence of synergism between atovaquone and chemotherapy by AMPK-dependent mitochondrial dysfunction.
- Authors: Xie F, Gong J, Tan H, Zhang H, Ma J
- Issue date: 2021 Sep 15
- Investigation of atovaquone-induced spatial changes in tumour hypoxia assessed by hypoxia PET/CT in non-small cell lung cancer patients.
- Authors: Bourigault P, Skwarski M, Macpherson RE, Higgins GS, McGowan DR
- Issue date: 2021 Dec 29