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2013|14 Annual Report Fraunhofer IGB

8 8 DEVELOPMENT OF A COMBINED IN-VITRO / IN-SILICO LUNG TUMOR MODEL FOR PERSONALIZED THERAPY Claudia Göttlich M.Sc. Lung cancer is the most common cancer-associated cause of death worldwide [1]. One reason for this is that chemotherapy treatment is limited to inoperable tumors. It has been shown in clinical studies that patients with activating mutations of the EGF receptor (EGFR, epidermal growth factor receptor) benefit from tyrosine kinase inhibitors (TKI) treatment, which act on the EGFR [2]. For example, the clinically available gefi- tinib treatment inhibits signal transduction through the EGF receptor, leading to slower growth or even tumor regression. For the development of personalized treatment strategies, biomarker profiles must be identified for patients groups that can be selected for targeted therapy. A promising new approach to this is the study of cellular signaling networks and their changes through targeted agents in tumor models that have specific mutations. Through this network analysis, modes of drug action can be understood and new therapeutic targets can be found. Tumor models should reflect the clinical situation as accurately as possible in the laboratory (in vitro) and their correlation with bioinformatics (in silico) models should be developed and used to evaluate complex signaling networks. Three-dimensional in-vitro lung tumor models The production of human three-dimensional (3D) tumor models in the Project Group Regenerative Technologies for Oncology is made on the SISmuc (small intestinal submucosa with preserved mucosa). This decellularized intestinal segment is derived from the complex structure of the BioVaSc (Biologi- cal Vascularized Scaffold [3]), which is composed primarily of collagen. We currently culture cell lines with (HCC827) and without (A549, H441) the EGFR activating mutation on the matrix (static culture) in order to map the genetic heterogene- ity of lung cancer. In-vitro tumor models reflect the clinical situation After 14 days of static culture, the cell lines form a largely homogeneous epithelial layer on the SISmuc and grow along the typical crypt structures. When compared to conventional two-dimensional (2D) culture plastic dishes, the cells have a lower division rate and altered expression of tumor markers in the 3D culture, which is much closer to the situation of patient tumors. The treatment of the cell line HCC827 carry- ing activating EGFR mutation with the TKI gefitinib leads to a reduced rate of division as well as increased tumor cell death. In contrast, the cell lines A549 and H441, which do not carry this mutation, have no change in these parameters with the treatment of gefitinib. We only observed significant effects of the drug gefitinib in the 3D tumor model. Thus, we achieve the same positive results that are described in the clinic in pa- tients with activating EGFR mutation in our in vitro 3D tumor model [4]. In silico modeling of the EGFR signaling networks In parallel with the in-vitro tumor model, a bioinformatics- based in-silico tumor model was developed in collaboration with the Department of Bioinformatics at the University of Würzburg (Prof. Dr. Thomas Dandekar), which was based on research and clinical data on the activation and network PHARMACY 21 0 % %ofKi67positivecells 2D 3D 100 % 80 % 60 % 40 % 20 % A549 HCC827

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