Investigating Hypoxia and the Potential for Atovaquone in Rhabdomyosarcoma
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Embargo End Date
2025-11-29
ICR Authors
Authors
Bernauer, C
Document Type
Thesis or Dissertation
Date
2025-05-29
Date Accepted
Abstract
Rhabdomyosarcomas (RMS) are rare aggressive childhood cancers with particularly poor prognosis at relapse. Hypoxia is a negative prognostic factor in cancer and is associated with cancer progression and resistance to radio- and chemotherapy. Hypoxia in RMS remains relatively unexplored. This project is aimed to assess the effect of hypoxia on RMS patient outcomes and test a novel therapeutic strategy based on hypoxia alleviation in RMS. To confirm the presence of hypoxia and assess blood vessel distribution, 40 diagnostic RMS samples were stained for hypoxia and endothelial cells. Hypoxia was present in more than half of the samples, and the location of hypoxia in relation to blood vessels was consistent with a diffusion-limited pattern of hypoxia. To evaluate the clinical relevance of hypoxia, a hypoxia gene signature was assessed in two RMS patient gene expression datasets. Overexpression of the signature significantly correlated with poorer patient outcomes in fusion negative RMS. To characterise the effect of hypoxia on chemotherapy response, eight RMS cell lines cultured in 2D were treated with vincristine and irinotecan, drugs used at relapse, under controlled oxygen conditions. This revealed a marked resistance to irinotecan in hypoxia. Atovaquone, an antimalarial being investigated for cancer treatment, was shown to alleviate hypoxia in 3D cultures of RMS cells. Combining atovaquone with irinotecan in these 3D cultures demonstrated potential therapeutic benefit and a variable but predominantly additive response in a panel of six RMS cell lines and an RMS patient-derived xenograft (PDX) cell culture. Cell lines that were most sensitive to the combination had higher levels of DNA damage with treatment compared to less sensitive cell lines. Lastly, it was shown that atovaquone inhibits RMS cell migration and that this effect may be associated with changes in actin fibres. This research underscores the role of hypoxia in influencing RMS patient outcomes and resistance to irinotecan. It also demonstrates the clinical potential of atovaquone, as a chemosensitiser and migration inhibitor, and that optimal response depends on multiple factors, including hypoxia.
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Sarcoma Mol Pathol