ESTRO 2024 - Abstract Book

S5195

Radiobiology - Microenvironment

ESTRO 2024

B16ova and MC38 spheroids containing a HRE-eGFP construct showed fluorescent cores indicating diffusion limited hypoxia. OXPHOS inhibitor IACS-010759 reduced hypoxia in these spheroids at 3 hours post treatment (Fig. 1). Interestingly, glucose uptake in these spheroids measured by [ 18 F]FDG uptake was decreased (MC38; P=0.0015, B16ova; P=0.0001, MOC1.3D5; P=0.0001) (Fig 1). Treatment of mice with IACS-010759 resulted in a reduction of pimonidazole fraction on MOC1.3D5 tumors sections (0.18 ± 0.06 vs. 0.08 ± 0.04) (Fig. 2). Blood glucose levels were not altered in these mice, but serum lactate was significantly increased following treatment with IACS-010759 (8.5 ± 1.7mM vs. 12.7 ± 1.4mM) (Fig. 2). Moreover, [ 18 F]FDG uptake in mice bearing MOC1.3D5 and B16ova tumors was significantly increased in lung (P=0.003), spleen (P=0.005), liver (P=0.04) and stomach (P=0.003) but not in the tumor (Fig. 2). [ 18 F]FDG uptake in the brain was decreased following IACS-010759 treatment (P=0.04).

Conclusion:

We showed that inhibition of OXPHOS can reduce hypoxia in both tumor cell spheroids and tumors, potentially increasing radio- and immunotherapy efficacy. However, tumor cells are metabolically plastic and can switch their metabolism from OXPHOS to glycolysis when OXPHOS is pharmacologically inhibited, resulting in an increased glucose uptake in tumor cell spheroids. In vivo we have seen a similar trend in other tissues, indicated by increased serum lactate levels and an increased [ 18 F]FDG uptake in several organs but not in the tumor. These observed effects call for caution when administering systemic OXPHOS inhibition, as adverse effects have been observed in clinical trials (6). More selective tumor targeting or less potent OXPHOS inhibitors may result in less toxicity in future studies.