ESTRO 2025 - Abstract Book

S3980

Radiobiology - Tumour radiobiology

ESTRO 2025

1 OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany. 2 Institute of Radiooncology – OncoRay, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany. 3 Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Gliwice, Poland. 4 Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. 5 National Center for Tumor Diseases (NCT), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany. 6 Department of Urology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. 7 Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Cancer Research Centre, Christie NHS Foundation Trust, Manchester, United Kingdom. 8 Institute for Molecular Systems Engineering and Advanced Materials, Heidelberg University, Heidelberg, Germany. 9 Experimental Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany Purpose/Objective: Prostate cancer (PCa) is the second most common cancer in men worldwide. About 15% of PCa patients are diagnosed with advanced disease. They have an increased risk of metastasis development (mPCa) with a five-year survival rate below 30%. The treatment response of mPCa is highly heterogeneous, whereas the therapeutic options and prognostic biomarkers for mPCa are limited. We recently identified aldehyde dehydrogenases ALDH1A1 and ALDH1A3 as critical regulators of PCa radioresistance and metas tases. This study aimed to delineate the mechanisms of this regulation and identify plasma-based biomarkers for mPCa treated with radiotherapy (RT). Material/Methods: The molecular mechanisms regulating ALDH/transforming growth factor beta (TGFB1)/matrix metalloproteinase 11 (MMP11) axes were analyzed by RNAseq, ChIP analysis, reporter assays, genetic silencing or overexpression, or modulating the gene transcription with different doses of the retinoic acid isomers, the products of ALDH catalytic activity. Expression levels of ALDH1A1, ALDH1A3, and MMP11 and their association with pathological parameters and clinical outcomes were analyzed in several publicly available patient transcriptomic datasets and in the own multicenter dataset from patients with high-risk and locally advanced PCa treated with ADT and RT (n = 430). The levels of MMP11 protein in plasma were analyzed by ELISA in independent cohorts of patients with androgen-sensitive oligometastatic PCa treated with metastasis-directed local ablative external beam radiotherapy (EBRT) (n = 31), localized or metastatic PCa treated with radical prostatectomy or taxane-based chemotherapy (n = 43) or age matched healthy donors (n = 5). A selected PCa cohort (n = 10) was used for plasma proteome profiles in the validation study. Results: ALDH1A1 and ALDH1A3 genes regulate TGFB1 expression in a RAR- and AR-dependent manner. TGF-β1 pathway further contributes to the positive regulation of the MMP11 expression in PCa cells. Knockdown of MMP11 in several PCa cell lines increased cell radiosensitivity. The MMP11 and TGFB1 expression was induced by stiff microenvironment and anchorage-free conditions. Transcription level of MMP11 was identified as a marker of clinical outcomes using independent datasets. The plasma MMP11 levels have shown a potential to differentiate between metastatic and non-metastatic PCa with high specificity (0.93) and sensitivity (0.9). Furthermore, MMP11 plasma levels had a significant association with PSA increase in patients with oligometastatic PCa treated with local ablative EBRT (p = 0.003). Conclusion: ALDH/TGFB1/MMP11 signaling contributes to the PCa metastases. MMP11 is a promising blood-based prognostic biomarker in patients with androgen-sensitive oligometastatic PCa receiving ablative EBRT to the metastatic lesions.

Keywords: MMP11, liquid biopsy, metastasis-directed RT