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bioRxiv · 10.1101/2022.11.27.518083

Hypoxic tumors are sensitive to FLASH radiotherapy

Leavitt, R. J.·Almeida, A.·Grilj, V.·Montay-Gruel, P.·Godfroid, C.·Petit, B.·Bailat, C.·Limoli, C. L.·Vozenin, M.-C.
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Abstract

Tumor hypoxia is a major cause of resistance to cancer treatments and especially to radiotherapy (RT) and we wanted to assess whether ultra-high dose rate FLASH RT could overcome this resistance. We engrafted tumor cells of various origins subcutaneously in mice to provide a reliable and rigorous way to modulate oxygen supply via vascular clamping or carbogen breathing. We irradiated tumors using a single 20 Gy fraction at either conventional (CONV) or FLASH dose-rate. Using multiple different subcutaneous tumor models, and in contrast CONV-RT, FLASH-RT retained anti-tumor efficacy under extreme hypoxia. These findings demonstrate that in addition to normal tissue sparing, FLASH-RT overcomes hypoxia-mediated tumor resistance. Follow-up molecular analysis using RNAseq profiling uncovered FLASH-specific inhibition of cell proliferation and translation as well as metabolic shifts that discriminated FLASH-RT from CONV-RT. These data provide new and specific insights into the mechanism of action and identify novel targets for intervention.

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Leavitt, R. J., Almeida, A., Grilj, V., Montay-Gruel, P., Godfroid, C., Petit, B., Bailat, C., Limoli, C. L., Vozenin, M.-C.. 2022-11-28. Hypoxic tumors are sensitive to FLASH radiotherapy. https://doi.org/10.1101/2022.11.27.518083

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