Prädiktion des Therapieansprechens beim kolorektalen Karzinom im multizellulären Sphäroidmodell: Sphero-PCT-Studie

Abstract

Background: Despite significant advances in conventional therapeutic approaches, the five-year overall survival rate of CRC patients with an intended curative resection (R0) is less than 50 %. Thus, the development of a relevant preclinical drug testing model is essential to identify novel therapeutic strategies. Methods and study design: The Spheroid Microtumor Model was established using primary tumor tissue samples from CRC patients. The spheroids were treated with both standard cytostatic drugs and molecular therapeutics, e. g. 5-FU, oxaliplatin and Cetuximab. The therapeutic effect of the drugs was tested with the TUNEL assay. The predictivity of the Spheroid Microtumor Model used in drug testing for the clinical situation is currently validated in a monocenter cohort study in the surgical clinic-Großhadern. Using log rank statistics with a power of 80 % and a type I error of 5 %, 58 patients with a CRC stage II and stage III will be randomized through a period of 18 months. Recurrence rate, disease free survival and overall survival will be compared with the exploratory analysis of the predictive effects of the Spheroid Microtumor Model. An interim analysis will be done after 11 patients failing standard therapy. Results: The Spheroid Microtumor Model closely mimics the tumor biology of microtumors in cancer patients, i. e. tumor differentiation, low tumor cell proliferation, tumor heterogeneity, interaction with stromal cells and drug resistance. Therefore, this test system allows the selection of the most therapeutically relevant drug candidates, i. e. cytostatics, antibodies and small molecules in different concentrations, combinations and sequences. In a recent pilot study we have demonstrated less efficacy of the conventional chemotherapy with 5-FU in CRC measuring the proliferation rate in the 3D model. In addition, we have shown the loss, changes and mutations of the most prominent indicators for 5-FU and oxaliplatin sensitivity. Conspicuously, target proteins for molecular therapeutics, such as EpCAM, CEA and EGF-R have been upregulated. Conclusion: Regarding some of the main obstacles in anti-cancer therapy, the Spheroid Microtumor Model closely reflects the complexity and heterogeneity of CRC. It represents a valid test system for ex vivo testing of conventional and molecular therapeutic strategies for the clinical situation.