Description:
<jats:title>Abstract</jats:title>
<jats:p>A common problem in translational research is the fact that findings from cell line experiments cannot be transferred one to one to the clinical setting, because each tumor consists of a variety of different cancer cells interacting with stroma cells, resulting in a highly variable response to drugs. In order to improve this situation, we previously developed an organoid culture based, preclinical drug testing platform suitable for the investigation of anticancer drug effects (cytotoxic drugs). In this study, we further advanced this model in order to measure effects of targeted drugs, such as small molecules and antibodies. Here we show that effects of therapeutic antibodies such as Trastuzumab (Herceptin®) and small molecules such as Gefitinib (Iressa®) were detectable using this model. Tumor tissue slices from colorectal and breast cancer patients were prepared and cultured according to Indivumed's standard operating protocols. First, we determined the degree of antibody diffusion into organoid cultures. Tissue slices were incubated with a commercially available antibody followed by immunofluorescence staining and microscopy. Functional effects of anti-HER-2 (Trastuzumab) treatment were examined in HER-2 positive and negative breast cancer tissue slices. In parallel, results have been confirmed in breast cancer cell lines (BT474 and MCF-7 cells) with positive and negative HER-2 expression. Trastuzumab treatment of breast cancer tissue slices and breast cancer cell lines showed a dose-dependent reduction of pAkt only in HER-2 positive tissues and cells. HER-2 expression levels of tissue slices and cells were previously analyzed by immunohistochemistry (IHC). IHC is a special feature of this model due to the capability to visualize drug effects within a tumor in individual cells.</jats:p>
<jats:p>In summary, the data revealed that large molecules such as antibodies diffuse into 400 μm thick cultured tissue slices reaching their target within 24 hours. Furthermore, we demonstrated that functional drug effects of therapeutic antibodies measured in secondary cell lines were reproduced in organoid cultures. The preclinical drug testing platform developed by Indivumed enables the examination of effects of classical chemotherapeutics and small molecules, as we have shown recently, as well as effects of larger molecules, such as antibodies. This implies that the model is suitable for a more comprehensive analysis of drug responses and in particular cellular responses to targeted drugs in a natural tumor microenvironment. This will ultimately allow for the determination of efficiency of anticancer drugs, help to prioritise drug candidates, support dose finding, identify promising indications for clinical trails and guide individualized therapy.</jats:p>
<jats:p>Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C228.</jats:p>