S2600
Radiobiology - Radiobiological modelling
ESTRO 2026
Digital Poster Highlight 2397
Digital Poster 2382
A validated multiscale framework coupling an agent-based model and TOPAS-nBio for simulating spheroid growth, hypoxia, and proton response Tiago A. Azevedo 1,2 , Inês A. Marques 2,3 , Eurico Pereira 2,3 , Mara Ribeiro 2 , Ana S. Pires 2,3 , Belén Cortés-Llanos 4 , Pablo F. Fernández 4 , Maria F. Botelho 2,3 , Célia T. Sousa 4,5 , Ana M. Abrantes 2,3 , Rui Travasso 1 , João Carvalho 1 1 Department of Physics, Centro de Física da Universidade de Coimbra (CFisUC), Coimbra, Portugal. 2 iCBR-Coimbra Institute for Clinical and Biomedical Research – Area of Environment, Genetics and Oncobiology (CIMAGO), Institute of Biophysics, Faculty of Medicine of the University of Coimbra, Coimbra, Portugal. 3 Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal. 4 Centro de Microanálisis de Materiales (CMAM), Universidad Autónoma de Madrid, Madrid, Spain. 5 Departamento de Física Aplicada e Instituto de Ciencia de Materiales Nicolás Cabrera, Universidad Autónoma de Madrid, Madrid, Spain Purpose/Objective: In silico modeling allows precise and efficient exploration of radiobiological behavior, extending what can be achieved with conventional experimental approaches. We developed and validated a novel multiscale framework coupling a Cellular Potts Model (CPM) for tumor growth with TOPAS-nBio (Schuemann et al., 2018), a Monte Carlo track structure code for radiation response. This coupled model was applied to simulate the growth dynamics and proton irradiation response of triple-negative breast cancer (TNBC) spheroids. Material/Methods: The framework was validated in two stages. First, the CPM was calibrated to reproduce 15-day growth dynamics using experimental data from spheroids of three TNBC lines (HCC1395, HCC1806, MDA- MB-231), and one non-tumorigenic line (MCF12A). Second, the experimental irradiation protocol was replicated in silico by simulating spheroid exposure to 10 MeV protons at doses ranging from 0 to 20 Gy. Per-cell dose deposition data from TOPAS-nBio was integrated back into the CPM. A modified two-lesion kinetic model (Stewart, 2001) was then applied within the CPM to determine cell fate. This model simulates double strand break (DSB) induction, repair, and misrepair, and was adapted to account for increased radiosensitivity in the presence of oxygen. Simulated viability was compared to experimental results obtained 7 days post-irradiation. Results: The coupled model accurately reproduces experimental spheroid growth dynamics for all four cell lines. As the spheroids evolved, the model successfully captured the development of oxygen gradients, leading to simulated regions of hypoxia, associated with radioresistance, and necrosis. A good agreement was found between simulated and measured spheroid radii (Weighted Mean Squared Error (WMSE): 2.52 μ m for HCC1395, 13.7 μ m for MCF12A, 24.1 μ m for MDA-MB-231, and 27.7 μ m for HCC1806). For the radiation response, TOPAS-nBio simulations provided initial DSB yields of 37 DSB/cell, with 78% classified as simple lesions and 15% attributed to direct effects. The overall simulated radiobiological response for the HCC1806 line showed excellent agreement with measured viability data, yielding a low WMSE of 1.92%.
First Long-Term NSCLC Spheroid Control Probability (SCP) Assay: A Quantitative Benchmark for Future Radio(chemo)therapy Testing Leonar S Prieto-Gonzalez 1 , Steffen Lange 2 , Marit Wondrak 1 , Leoni A Kunz-Schughart 3,4 1 Tumor Patophysiology, OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz- Zentrum Dresden-Rossendorf, Dresden, Germany. 2 DataMedAssist, HTW – University of Applied Sciences, Dresden, Germany. 3 Tumor Pathophysiology, Institute of Radiooncology – OncoRay, Helmholtz- Zentrum Dresden-Rossendorf (HZDR) and OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany. 4 National Center for Tumor Diseases (NCT), NCT/UCC Dresden, Faculty of Medicine and University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany Purpose/Objective: Robust preclinical methods to evaluate long-term, curative radiotherapy outcomes remain underdeveloped. While three- dimensional multicellular tumor spheroids (MCTS) effectively mimic various therapeutically relevant pathophysiological characteristics, a standardized, quantitative benchmark for their long-term control post-irradiation has not been established. The objective of our work is to fill this critical methodological gap by establishing the first comprehensive Spheroid Control Probability (SCP) assay for Non- Small Cell Lung Cancer (NSCLC) MCTS models, thereby generating a foundational reference dataset. Material/Methods: Two NSCLC cell lines, NCI-H460 and NCI-H23, were cultured as standard (sS, Ø 350-400 µm) and large (LS, Ø 600-650 µm) MCTS. At day 4 in culture, they received single-dose photon irradiation (0-28 Gy) and were monitored for 60 days post-treatment using a standardized workflow coupled with semi-automated image analysis. Treatment outcome was defined by the proportion of growth-controlled spheroids, allowing for the calculation of two key endpoints: the intermediate (non-curative) endpoint, Relative Growth Delay (GD), and the long-term (curative) endpoint, Spheroid Control Dose 50% (SCD50). Results: The approach revealed a plethora of relapse morphologies of NSCLC MCTS upon irradiation, as well as critically distinct radiosensitivity profiles of the two models. The NCI-H23 MCTS are highly radiosensitive (SCD50 ≈ 6-7 Gy) regardless of their size. In contrast, the NCI-H460 MCTS model is significantly more radioresistant and exhibits a pronounced size-dependency, with its SCD50 increasing from 12.5 Gy (sS) to 19.0 Gy (LS). These divergent curative outcomes were supported by time-to-relapse (Kaplan-Meier) documentations, revealing more frequent and earlier relapses in the NCI-H460 MCTS cohorts. The intermediate endpoint to some extend but not fully corroborate these findings. Conclusion: This work provides a quantitative benchmark for long-term radioresponse in different NSCLC MCTS, serving as essential ground- truth to (i) validate the predictive power of short-term assays as surrogates for curative outcomes, and (ii) develop a test platform for more complex therapeutic scenarios in NSCLC MCTS including
fractionated regimens and proton therapy. Keywords: SCP, radiosensitivity, NSCLC
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