ColoNet project

ColoNet – A systems biology approach for integrating molecular diagnostics and targeted therapy in colorectal cancer undefinedmore information about ColoNet

The major objective of the project is to accomplish an in silico network of genetic, epigenetic and signaling processes to tailor diagnostics with predictive information for therapies targeting receptor tyrosine kinases (e.g. EGFR) in colorectal cancer. The network model is expected to provide diagnostic guidance for the improvement of therapy response prediction by achieving an in-depth functional understanding of receptor-mediated signaling and downstream processes. The core model will consist of a “static” colon-specific signaling network model that serves as a framework for integrating detailed kinetic models of MAPK and Wnt pathways, existing genetic/epigenetic information, high-throughput data, knowledge on predictive markers obtained by literature mining, and physiologically relevant data. The dynamics of MAPK and Wnt pathways, which are crucial for targeted therapies, will be subjected to detailed mathematical modeling based on results from focused experimental measurements. Once detailed models of pathways, key signaling nodes, feed-back loops and marker combinations are established, we will turn the static network into a dynamic model in an iterative process. Finally, this approach should generate a tool for the in silico evaluation of novel markers or combinations of them for an improved therapy prediction. We expect that our model will also be useful for other types of cancer and related predictive diagnostics.

Subproject:  Molecular characterization of experimental models
Key features of the project are experimental models extensively characterized for para-meters known or expected to be involved in therapy efficacy. A significant proportion of information is available from the partners’ previous work and through public databases, while the generation of missing information will produce a high experimental standardization and ensure maximal clinical relevance.

Subproject: Assessing the dynamics of key pathways following specific intervention
This project will focus on two paradigmatic oncogenic pathways: the receptor-MAPK and the Wnt signaling systems, directly relevant for prediction and therapy and including the functionally associated receptors and underlying genetic and epigenetic alterations. For dynamic modeling at the systems level, multi-level data harboring functional and quantitative information will be gathered after defined perturbation of potential predictive markers. The focus will be on direct pathways intervention effects, the dynamics of such processes and effects on potentially associated “tumor” markers, e.g. transcriptional and DNA-methylation markers.

Support

Supported by: BMBF, MedSYS

Head

Prof. Dr. rer.nat. Reinhold Schäfer
Deputy Director Charité Comprehensive Cancer Center (Translational Cancer Research)
t: +49 30 450 564 640