Spher4Sys

Project Image:
Title of the project:

Spher4Sys

Teasertext:
Systems biological method for the development of preclinical lead structures using an in vivo near spheroid test system
Summary:
Systems biological method for the development of preclinical lead structures using an in vivo near spheroid test system
Start:
01.04.2009
End:
31.03.2012
Project leader:
Dr. Michael Pawlak
Project funding:
  • Bundesministerium für Bildung und Forschung (BMBF)
Project management:
  • Forschungszentrum Jülich
Funding reference number:
0315284B
Text:

A paradigm shift in the development of cancer drugs is the goal of a BMBF-funded initiative that the NMI is pursuing with clinical researchers, biotech companies and bioinformaticians. Instead of individual proteins (targets), which indicate the efficacy of substances in the simple cell test system, 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. Their biological properties are very similar to those of cancer patients.

Description:

The aim of this BMBF-funded initiative is the development and validation of a systems biological cellular test system for the development of new cancer drugs. This is done with a focus on the indication colorectal cancer. In tumors, gene mutations lead to characteristic molecular changes in different cellular signal transduction pathways (e.g. MAP kinase or Wnt signalling pathway). The involved key proteins will be detected by array-based throughput analyses. For the new approach in drug development, a complex phenotype will determine intracellular signal transduction - directly in tumor-like cell assemblies - instead of single proteins (targets), which today indicate the efficacy of substances in the simple cellular test system. The new approach is based on the tissue culture technology of Spherotec GmbH, which enables the production of multicellular spheroids in large numbers from primary tumour tissue. The biological properties of these spheroids are very similar to those of cancer patients and are used at the NMI to generate patterns of molecular changes that map the complex effects of 4SC's new preclinical drug candidates. The data will open up the possibility of identifying biomarkers for the antitumoral efficacy of the substances. The systems biology approach aims to make an important contribution to the reduction of failure rates in later stages of clinical drug development.
The NMI subproject uses reverse-phase protein microarrays to detect changes (patterns) in cellular signal transduction that occur before/after the 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 are 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 of patients).

Project partners:
  • 4SC AG, Martinsried
  • quattro research GmbH, Martinsried
  • Spherotec GmbH, Martinsried
  • ZBIT Zentrum für Bioinformatik, Universität Tübingen