Spher4Sys

A paradigm shift in the development of anti-cancer drugs is the goal of a BMBF-funded initiative that the NMI is working on with clinical researchers, biotech companies and bioinformaticians. Instead of individual proteins (targets) indicating the efficacy of substances in simple cell assays, a complex phenotype, intracellular signal transduction, is determined directly in tumor-like cell assemblies using reverse protein arrays. The new approach is based on the tissue culture technique of Spherotec, which allows the production of multi-cellular spheroids in large numbers from primary tumor tissue. These are very similar in their biological properties to the tumors of cancer patients.

The goal of this BMBF-funded initiative is the development and validation of a systems biology cellular test system for the development of new cancer drugs. This is being done with a focus on the indication of colorectal cancer. In tumors, gene mutations lead to characteristic molecular changes in different cellular signal transduction pathways (e.g. MAP kinase or Wnt signaling pathway). The key proteins involved will be tracked down using array-based throughput analysis. For the new approach in drug development, instead of single proteins (targets), which today indicate the efficacy of substances in a simple cellular assay system, a complex phenotype will determine the intracellular signal transduction - directly in tumor-like cell assemblies.  The new approach is based on the tissue culture technology of the company Spherotec GmbH, which allows multicellular spheroids to be produced in large numbers from primary tumor tissue. These are very similar in their biological properties to the tumors of cancer patients and are used at the NMI to generate patterns of molecular changes that map the complex effects of new preclinical drug candidates from the company 4SC. The data open up the possibility of identifying biomarkers for the antitumor efficacy of the substances. The systems biology approach aims to make an important contribution to reducing failure rates in later stages of clinical drug development.
In the NMI subproject, reverse-phase protein microarrays are used to detect changes (patterns) in cellular signal transduction that occur before/after treatment of tumor spheroids with known reference and preclinical lead structures (Spherotec subproject) (multiple response profiling). 100-200 relevant proteins (regulators/effectors) of known signal transduction cascades will be defined and detected. Complex expression and activation patterns are generated from the measurements. Results of spheroid systems from preclinical samples (cell and animal models) are compared with those from later clinical samples (colon cancer tissues from patients).