Mitochondrial inhibitor atovaquone increases tumor oxygenation and inhibits hypoxic gene expression in patients with non-small cell lung cancer

Author: 

Skwarski, M
McGowan, D
Belcher, E
Di Chiara, F
Stavroulias, D
McCole, M
Derham, J
Chu, K
Chauhan, J
O'reilly, D
Harris, B
Macklin, P
Bull, J
Green, M
Rodriguez Berriguete, G
Prevo, R
Campo, L
Ferencz, P
Qi, C
Holmes, J
O'Connor, J
Gleeson, F
McKenna, W
MacPherson, R
Higgins, G

Publication Date: 

17 February 2021

Journal: 

Clinical Cancer Research

Last Updated: 

2021-10-15T13:19:25.193+01:00

DOI: 

10.1158/1078-0432.CCR-20-4128

abstract: 

<strong>Purpose:</strong> 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).
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<strong>Patients and methods:</strong> Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: Cohort 1 received oral atovaquone at the standard clinical dose 750 mg twice-daily whilst Cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Inter-cohort comparison of hypoxia gene expression signatures using RNAseq from resected tumors was performed.
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<strong>Results:</strong> 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 -28.0% (95% 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% to 74%) lower in Cohort 1 compared to Cohort 2 (p=0.004), adjusting for cohort, tumor volume and baseline HV. A key pharmacodynamic 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.
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<strong>Conclusions:</strong> This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant anti-tumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC.

Symplectic id: 

1159910

Submitted to ORA: 

Submitted

Publication Type: 

Journal Article