Development of Organotypic Cancer Models for the Identification of Individualized Cancer Therapies

The response to anti-cancer drugs is determined by the genetic make-up of cancer cells and the cross-talk between tumor cells and its surrounding stromal components. In the present study we have developed experimental strategies to assess drug efficacies in complex organotypic cancer models. We have established advanced cell-and-tissue-engineering technologies for the cultivation of miniaturized tumor-tissue slices for a prolonged period of time in culture. After surgery and tissue dissection, the slices retained the complex tissue architecture of tumors for at least seven days. The tumor cells still proliferated in vitro and apoptosis was only weakly detected in peripheral areas of the tumor. To determine the applicability of precision-cut slices for drug discovery, we treated breast cancer specimen with the HER2/HER1 inhibitor Lapatinib for 72 hours and analyzed the extent of apoptosis in the tissues. We detected massive apoptosis in tumors that expressed significant levels of HER2 protein whereas HER2-negative tumors only weakly responded to the treatment. In a further approach we developed customized 3-dimensional (3D) co-culture models consisting of lung cancer cells and tumor-associated fibroblasts that were embedded in Matrigel®/collagen extracellular matrices. The fibroblasts strongly increased the invasive capabilities of the cancer cells, but treatment with the ALK/MET inhibitor Crizotinib almost completely abrogated cancer cell invasion. Taken altogether, we could demonstrate that both the cancer tissue slices and the customized coculture models might represent suitable experimental tools for the determination of drug efficacy in vitro. They could be used to test the efficacy of a larger number of combinatorial therapies to select the most appropriate drugs for individual patients. As a result organotypic tissue models might open up new vistas in the field of personalized medicine and in clinical oncology.