ESTRO 2025 - Abstract Book

S4007

Radiobiology - Tumour radiobiology

ESTRO 2025

Material/Methods: We employed different prostate cancer models in vitro and in vivo, CRISPR technology and viability assays.

Results: Applying CRISPR screen technologies, we found that loss of components of the Shieldin complex confers enhanced Polθ inhibitor-mediated radiosensitisation in HR-proficient cell models. Data mining of clinical samples databases highlighted that a significant subset of prostate cancers (~5-10%) carry homozygous deletions in SHLD2 co-occurring with PTEN loss, which may open a clinically relevant collateral vulnerability. Consequently, we focused our further efforts on SHLD2 in prostate cancer models. To validate the results of our screens, we generated several SHLD2 KO clones derived from different cancer cell lines, including two HR-proficient prostate cancer cell lines. Viability assays demonstrated that SHLD2 KO models are significantly more susceptible to Polθ inhibition-mediated radiosensitisation than wild type (WT) counterparts. Reintroduction of SHLD2 gene in SHLD2 KO cells reversed the increased radiosensitisation effect of Polθ inhibition, providing further evidence that this enhanced radiosensitisation phenotype is specifically caused by SHLD2 loss. We next tested the effect of Polθ inhibition and radiotherapy in WT and SHLD2 KO prostate cancer xenografts. The combination of Polθ inhibitor with radiotherapy significantly reduced tumour growth compared to radiotherapy alone in the SHLD2 KO xenografts, while this effect was much less pronounced in the WT xenografts. In line with our previous in vivo study, the combination treatment was well tolerated. Conclusion: Our findings demonstrate that Polθ inhibition in combination with radiotherapy is an effective treatment for tumours carrying deficiencies in the SHLD complex. Given the relevant incidence of SHLD2 loss in prostate cancer and the clinical development of Polθ inhibitors, our results provide a patient selection biomarker that paves for the clinical development of this combination treatment regimen. References: 1. Rodriguez-Berriguete et al. Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models. Clin Cancer Res. 2023 Apr 14;29(8):1631-1642. 2. Zatreanu et al. Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nat Commun. 2021 Jun 17;12(1):3636. 3. Belan et al. POLQ seals post-replicative ssDNA gaps to maintain genome stability in BRCA-deficient cancer cells. Mol Cell. 2022 Dec 15;82(24):4664-4680.e9. Keywords: DNA damage, DNA polymerase theta, SHLD2 Poster Discussion A novel fuzzy statistical approach for texture features with higher reliability and modeling performance in radiomics analysis of oropharyngeal cancer Jin Cao 1 , Xinzhi Teng 1 , Ta Zhou 1,2 , Yuanpeng Zhang 1,3,4 , Jiang Zhang 1 , Jing Cai 1,4 1 Department of Health Technology and Informatics, The Kong Kong Polytechnic University, Hong Kong, China. 2 School of Electrical and Information Engineering, Jiangsu University of Science and Technology, Zhenjiang, China. 3 Department of Medical Informatics, Nantong University, Nantong, China. 4 N/A, The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China Purpose/Objective: Radiomics reliability is critical for clinical application. Reliable features are identified using intraclass correlation (ICC) values derived from test-retest or perturbed data [1]. However, lower ICC does not equivalent to the useless of this feature, and dismissing them may lead to resource inefficiency. This study aims to enhance the inherent reliability 3244