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Mechanistic Modeling of DNA Repair and Cellular Survival Following Radiation and Temozolomide for Glioblastoma Multiforme Cells

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H Oesten

H Oesten1,2,3*, A Jakob2,4, A Luehr2,4, C von Neubeck2,4, C Grassberger1, S McMahon5, H Paganetti1, W Enghardt2,3,6,7,8, M Krause2,3,4,6,9 (1) Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA (2) OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universitaet, Dresden, Germany (3) Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Institute of Radiooncology - OncoRay, Dresden, Germany (4) German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany, Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany (5) Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, N. Ireland (6) Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany (7) Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany; (8) German Cancer Consortium, Dresden, Germany. (9) National Center for Tumor Diseases, Partner Site Dresden, Dresden, Germany


SU-I-GPD-T-657 (Sunday, July 30, 2017) 3:00 PM - 6:00 PM Room: Exhibit Hall

Purpose: In this study, we modified a mechanistic radiation-damage-induction/repair model [McMahon et al, Sci Rep 2016] to include temozolomide-induced damage and modification of radiation-repair for comparison with experimental data.

Methods: Based on a previously developed mechanistic radiation model of DNA repair and cell survival, we compared model predictions to experimental data in five Glioblastoma multiforme (GBM) cell lines with radiation-only and neoadjuvant temozolomide treatments. The radiation-only model incorporates three cell line specific parameters: cell-cycle distribution, number of chromosomes (NoC) and genome size. The first two were experimentally obtained via flow cytometry and Giemsa stains; the genome size was obtained by fitting a linear function of the experimentally characterized NoC data. We then modified the radiation-only model to allow for consideration of the effects of temozolomide, i.e. inducing double-strand-breaks (DSB), cell-cycle arrest, and decreasing repair.

Results: The radiation-only model agreed with the in-vitro measurements within the experimental error. To model temozolomide-only, we implemented a constant DSB induction for the duration of exposure, yielding DSB induction rates of 100-500/h. Combining the two models and comparison to the experimental data for temozolomide followed by radiation yielded acceptable results only in one cell line, suggesting an additive mechanism. For four cell lines, simulated results deviated significantly from measurements, necessitating tuning the processes temozolomide is known to interfere with. By reducing the number of cycling cells and decreasing the repair fidelity (1-3%), the model could successfully be adapted to the experimental data for all but one cell line being radioresistant and temozolomide-sensitive at the same time, leading to a breakdown of assumptions in DSB-induction/repair.

Conclusion: We successfully modified a mechanistic radiation DSB-induction/repair framework to model the DSB-induction and repair caused by temozolomide in four experimentally characterized GBM cell lines. This model could provide insight into cell line specific mechanisms of synergy for combined modality treatments.

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