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

Journal article

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 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.
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 -28.0% (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.
Conclusions: 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.

Authors: Skwarski, M; McGowan, D; Belcher, E; Di Chiara, F; Stavroulias, D

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Association for Cancer Research
• Journal: Clinical Cancer Research
• Volume: 27
• Issue: 9
• Pages: 2459-2469
• Publication date: 2021-02-17
• Acceptance date: 2021-02-11
• DOI: 10.1158/1078-0432.CCR-20-4128
• EISSN: 1557-3265
• ISSN: 1078-0432
• Language: English
• Keywords: FMISo PET-CT; OXPHOS inhibitor; tumor hypoxia; FFR; NSCLC; atovaquone