3d Tumor Models For The Assessment Of Molecular Targeted Therapies

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL It is becoming increasingly apparent that the interaction between the tumor and the surrounding stromal cells is critical to tumor growth, invasion and metastasis. These paracrine interactions can profoundly alter EMT profiles and modulate key growth factor signaling cascades which can lead to altered responsiveness to molecular targeted therapies such as EGF-R TKI inhibitors. We have developed a novel 3D tumor growth assay, where the paracrine interaction between tumor derived fibroblasts and epithelial cells are restored. Utilizing luminescent and fluorescent labeled cell populations we are able to monitor tumor-microenvironment driven tumor growth in the presence of targeted therapies in comparison to standard platinum dublet therapies. Primary tumor associated fibroblasts and mesenchymal stem cells drive growth and proliferation of non-small cell lung cancer cell lines of adenocarcinoma (A549, NCI-H358, NCI-H460) and squamous subtypes (SK-MES1, H226) as well as early stage disease (NCI-H322M). The paracrine interaction promotes 3D structure formation and invasion into laminin rich basement membrane extract. Cells grown in 3D assays show a slowed proliferation and lower sensitivity to anti-mitotic agents such as paclitaxel. As proof of concept we show that responsiveness to EGF-R TKI is significantly decreased in the presence of HGF secreting stromal cells irrespective of EGF-R and KRAS mutational status. The 3D growth assay provides a more tumor microenvironment relevant model for pre-clinical testing of molecular targeted therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 555. doi:10.1158/1538-7445.AM2011-555