Prediction of the therapeutic response in colorectal cancer patients using the Spheroid Microtumor Technology

Abstract

22178 Background: Colorectal cancer (CRC) is the third most common malignancy and the fourth most frequent cause of cancer death worldwide. 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%. Therefore, the development of a relevant preclinical drug testing model is essential to identify novel therapeutic strategies. Methods: The Spheroid Microtumor Model was established using primary tumor tissue samples from CRC patients. The spheroids were treated in vitro with both standard cytostatic drugs and molecular therapeutics, e.g. 5-FU, oxaliplatin and Cetuximab. 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. Thus, using log rank statistics with a power of 80% and a type I error of 5%, 58 patients with a CRC stage II (high risk) and stage III will be randomized through a period of 24 months. 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. We have shown the loss, changes and mutations of the most prominent indicators for 5-FU sensitivity, i.e. thymidylate synthase, thymidine phosphorylase and a higher activation of the dihydropyrimidine dehydrogenase in a variety of CRC tumors. Conspicuously, target proteins have been upregulated, such as EpCAM, CEA, MUC-1, EGF-R and CD44v6. Conclusions: The Spheroid Microtumor Model represents a valid test system for ex vivo testing of conventional and molecular therapeutic strategies for the clinical situation. The combination of molecular target profiling and functional drug testing is a prerequisite for individualized cancer therapy. No significant financial relationships to disclose.