S2584
Radiobiology – Normal tissue radiobiology
ESTRO 2026
patients. However, it often involves unavoidable irradiation of normal tissues surrounding the tumor, including the salivary glands. We have previously shown radiation preferentially induces cellular senescence in the salivary gland stem/progenitor cell niche contributing to hyposalivation. Clearance of senescent cells using senolytic drugs could be a therapeutic strategy to ameliorate radiotherapy- induced xerostomia. Objective: To develop a drug screening method to identify potent senolytic drugs insalivary gland organoids and test for regeneration capacity following senolytic treatment. Material/Methods: Materials & Methods: (Sham-)irradiated salivary gland organoids were treated with different doses of candidate senolytic drugs. As a measure of senolytic activity a Caspase-3/7 fluorogenic substrate was added together with the selected drugs. Increases in salivary gland organoid apoptosis following treatment, inferred from Caspase-3/7 activity, were detected in real-time using an IncuCyte S3. Drug concentrations that efficiently induced apoptosis in irradiated cells but were not or less toxic to unirradiated cells were selected to further verify the elimination of senescent cells and corresponding changes in the organoid forming efficiency (OFE). The top candidate was tested in vivo in a mouse model of radiation-induced hyposalivation using C57BL/6 mice treated 8-weeks post IR. Results: Results: Of the senolytics tested, Nutlin3a, an MDM2 inhibitor and P53 activator, increased organoid self- renewal capacity after irradiation and had the most favourable toxicity profile. Accordingly, treatment with Nutlin3a resulted in a reduction of senescent markers in irradiated organoids and a transcriptional increase in p53 target genes. Administration of Nutlin3a in irradiated mouse salivary glands elicited a regenerative response and resulted in a robust increase in saliva production as early as two weeks after administration. Conclusion: Conclusion: We conclude that screening for drugs that show senolytic activity without hampering stem cell expansion (as measured by OFE) may be a promising methodology for the identification of compounds with potential applications in post-radiotherapy regenerative medicine. References: 1. Peng, X., et al., Cellular senescence contributes to radiation-induced hyposalivation by affecting the stem/progenitor cell niche. Cell death & disease, 2020. 11(10): p. 854-854.2. Marmary, Y., et al., Radiation- Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation. Cancer Res, 2016. 76(5): p. 1170-80.3. Chang, J., et al., Clearance of senescent cells by ABT263 rejuvenates
Figure 1. Differentially expressed microRNAs in breast cancer patients comparing overall toxicity between cases (n=74) and controls (n=62) in the discovery cohort. A Heatmap of microRNAs differentially expressed between patients with and without toxicity (adjusted p ≤ 0.05, |fold change| ≥ 1.5), based on hierarchical clustering of patients (columns). B Volcano plot showing microRNAs with adjusted p ≤ 0.05 (blue) and those also meeting |fold change| ≥ 1.5 (purple). Conclusion: We identified a four-miRNA signature in whole blood that shows potential as a biomarker for predicting late radiotherapy toxicity in breast cancer patients.Funding: RADprecise: ERAPerMed JTC2018 (ERAPERMED2018-244 and SLT011/18/00005); REQUITE: European Union’s Seventh Framework Programme for research, technological development, and demonstration under grant agreement no. 601826 Keywords: blood microRNAs, late side effects, breast cancer A two-step organoid-based screen identifies MDM2 inhibition as a senolytic strategy to ameliorate radiation-induced salivary gland dysfunction Abel Soto-Gamez 1,2 , Yi Wu 1 , Eline Hageman 1,2 , Uilke Brouwer 1,2 , Davide Cinat 1,2 , Arjan Vissink 3 , Marco Demaria 4 , Lara Barazzuol 1,2 , Sarah Pringle 5 , Rob P Coppes 1,2 1 Radiation Oncology, UMCG, Groningen, Netherlands. 2 Biomedical Sciences, UMCG, Groningen, Netherlands. 3 Oral and Maxillofacial Surgery, UMCG, Groningen, Netherlands. 4 European Research Institute for the Biology of Ageing (ERIBA), UMCG, Groningen, Netherlands. 5 Rheumatology and Clinical Immunology, UMCG, Groningen, Netherlands Purpose/Objective: Background: Radiotherapy treatment significantly improves the survival of head and neck cancer Proffered Paper 4646
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