دورية أكاديمية
Mitochondrial Inhibitor Atovaquone Increases Tumor Oxygenation and Inhibits Hypoxic Gene Expression in Patients with Non-Small Cell Lung Cancer.
| العنوان: | Mitochondrial Inhibitor Atovaquone Increases Tumor Oxygenation and Inhibits Hypoxic Gene Expression in Patients with Non-Small Cell Lung Cancer. |
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| المؤلفون: | Skwarski, M, McGowan, DR, Belcher, E, Di Chiara, F, Stavroulias, D, McCole, M, Derham, JL, Chu, K-Y, Teoh, E, Chauhan, J, O'Reilly, D, Harris, BHL, Macklin, PS, Bull, JA, Green, M, Rodriguez-Berriguete, G, Prevo, R, Folkes, LK, Campo, L, Ferencz, P, Croal, PL, Flight, H, Qi, C, Holmes, J, O'Connor, JPB, Gleeson, FV, McKenna, WG, Harris, AL, Bulte, D, Buffa, FM, Macpherson, RE, Higgins, GS |
| المساهمون: | O'Connor, James Patrick |
| بيانات النشر: | AMER ASSOC CANCER RESEARCH |
| سنة النشر: | 2021 |
| المجموعة: | The Institute of Cancer Research (ICR): Publications Repository |
| الوصف: | 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 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% [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. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | Print-Electronic; application/pdf |
| اللغة: | English |
| تدمد: | 1078-0432 1557-3265 |
| العلاقة: | Clinical cancer research : an official journal of the American Association for Cancer Research, 2021; https://repository.icr.ac.uk/handle/internal/4486Test |
| DOI: | 10.1158/1078-0432.ccr-20-4128 |
| الإتاحة: | https://doi.org/10.1158/1078-0432.ccr-20-4128Test https://repository.icr.ac.uk/handle/internal/4486Test |
| حقوق: | https://www.rioxx.net/licenses/under-embargo-all-rights-reservedTest |
| رقم الانضمام: | edsbas.A5292EBB |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 10780432 15573265 |
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| DOI: | 10.1158/1078-0432.ccr-20-4128 |