ESTRO 2024 - Abstract Book

S5194

Radiobiology - Microenvironment

ESTRO 2024

tissues showed increased iron accumulation after both FLASH and conventional RT. Iron accumulation corresponded to lipid peroxidation as well.

Conclusion:

Therefore, our data suggest that iron-mediated lipid peroxidation and resulting ferroptosis may be a possible mechanism of FLASH effect.

Keywords: FLASH, iron, lipid peroxidation

327

Proffered Paper

Inhibition of OXPHOS induces a metabolic switch and reduces hypoxia in immunocompetent tumor models

Daan F. Boreel 1,2 , Anne P.M. Beerkens 1,2 , Paul N. Span 3 , Johannes P.W. Peters 1 , Milou Boswinkel 2 , Gosse J. Adema 1 , Sandra Heskamp 2 , Johan Bussink 1 1 Radboudumc, Radiation Oncology, Nijmegen, Netherlands. 2 Radboudumc, Medical Imaging, Nijmegen, Netherlands. 3 Nijmegen, Radiation Oncology, Nijmegen, Netherlands

Purpose/Objective:

Limited diffusion of oxygen in combination with increased oxygen consumption leads to chronic hypoxia in most solid malignancies (1). This scarcity of oxygen is known to induce radioresistance, but also leads to a more immunosuppressive microenvironment and immunotherapy resistance (2, 3). By the inhibition of OXPHOS, using mitochondrial complex I inhibitor IACS-010759, we hypothesize the oxygen demand of the tumor can be decreased (4). In turn this might lead to a durable normalization of the oxygen concentration, increasing the efficacy of radio- and immunotherapy and its combination (5).

Material/Methods:

Spheroids were produced of murine tumor cells (MC38, MOC1.3D5 and B16ova) containing a HIF1-a responsive element (HRE)-eGFP construct. Using a Live-Cell Analysis System, fluorescence of spheroids to quantify diffusion limited hypoxia. To measure glucose uptake, [ 18 F]FDG (150 kBq) was added to the medium of spheroids. After incubation, spheroids were washed and cell associated activity was measured using a γ-counter. C57BL/6 mice bearing B16ova or MOC1.3D5 tumors (± 100 mm3) were treated with OXPHOS inhibitor IACS-010759 (10mg/kg) for 4 consecutive days. 1 hour before sacrifice mice were injected with [ 18 F]FDG (10 MBq) and pimonidazole (hypoxia marker). [ 18 F]FDG uptake in selected organs was determined by ex vivo activity counting. Hypoxic fraction was determined by immunohistochemical staining of pimonidazole.

Results: