ESTRO 2024 - Abstract Book

S5397

Radiobiology - Tumour biology

ESTRO 2024

Results:

We have observed that the hypoxia marker HIF1-α, as well as the gene expression related to OXPHOS, were significantly elevated in the previously as radioresistant classified PDO subcohort. Single treatment with Oligomycin A reduced the baseline cell viability in a concentration dependent manner. Concentrations of 0.8 μg/ml, 1.6 μg/ml, 3.2 μg/ml and 6.4 μg/ml were used for further experiments, as the PDO lines exhibited varying degrees of response to the inhibitor. We observed a radiosensitizing effect after combined treatment of inhibitor and irradiation compared to irradiated PDOs alone. Adding Oligomycin A 24 h before irradiation was more sufficient compared to the treatment added 1.5 h before irradiation. The radiosensitization was already detectable at 4 Gy.The 3D microscopy was established to determine the morphological characteristics after combined treatment. As expected, the organoids showed a decrease in diameter after irradiation and Oligomycin A treatment.

Conclusion:

Hypoxia is a well know reason for radioresistance in cancer. In line with this, more positive HIF-1a stained cells were found in the radioresistant PDO subgroup. Linked with the elevated OXPHOS pathway, which indicates a higher O2 consumption, OXPHOS inhibition is a reasonable potential target for radiosensitization. Oligomycin A showed an antiproliferating effect as single treatment as well as a radiosensitizing effect in PDOs. As PDOs reflect the geno- as well as phenotype of the individual patients’ tumor these results offer the opportunity of translation into clinical application. Oligomycin A and OXPHOS-inhibitors in general maybe hold the potential to open the possibility for RT to overcome radioresistant pancreatic cancer. A validation and further characterization of our findings in vitro as well in vivo are ongoing.

Keywords: radiosensitization, patient-derived organoids,

References:

1. Park, W., A. Chawla, and E.M. O'Reilly, Pancreatic Cancer: A Review. Jama, 2021. 326(9): p. 851-862. 2. Tiriac, H., et al., Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. Cancer Discov, 2018. 8(9): p. 1112-1129. 3. Masoud, R., et al., Targeting Mitochondrial Complex I Overcomes Chemoresistance in High OXPHOS Pancreatic Cancer. Cell Rep Med, 2020. 1(8): p. 100143. 4. Hao, W., et al., Oligomycin-induced bioenergetic adaptation in cancer cells with heterogeneous bioenergetic organization. J Biol Chem, 2010. 285(17): p. 12647-54.

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