Spher4Sys: Systems biology based approach for preclinical lead compound development using an in-vivo like spheroid test system

Short description:


The project is aiming towards a paradigm shift in cancer drug discovery and development, where the complex phenotype in cancer is the relevant target and read-out for the screening process, and not the single drugable target protein. Our goal is to generate and introduce clinical relevant phenotype information already early in the drug discovery and development process in order to reduce late substance failure and correlate chemical structures with clinical phenotypes.

To this end, the pharma company 4SC will provide reference substances and small molecule compounds from its unique library, as well as leads for different classes of targets. Spherotec will provide spheroid test systems formed from clinical patient material and treated with the compounds selected by 4SC. To profile the cancer phenotypes, the spheroids are subjected to Reverse-Phase Protein Array (RPPA) analysis, whereby the expression and phosphorylation states of more than 100 proteins are measured quantitatively.

In this subproject, we mapped the RPPA analytes to diverse cancer-specific pathways, in order to put the high-dimensional cancer phenotypes into the biological context of cancerogenesis. To identify or confirm the pathways targeted by diverse preclinical compounds, we extract subgraphs of the signalling networks which are enriched with deregulated proteins, showing differential expression and/or phosphorylation between treated samples and controls.

Modeling drug action on a systems level, we generate hypothesis about the mode of action and potential targets of preclinical leads to guide lead optimization. Furthermore, we correlate the therapeutic efficacy of leads with observed cancer phenotypes to facilitate a more effective, individualized drug therapy of colon cancer.


Project partners:


4SC, Muenchen
NMI, Reutlingen
Spherotec, Muenchen
Quattro Research, Muenchen

Funding:


Spher4Sys is part of the MedSys project funded by the Federal Ministry of Education and Research (BMBF).

Contact: Johannes Eichner, Raum C303, Tel. (07071) 29-70436, eichner at informatik.uni-tuebingen.de

Publications

[1] Johannes Eichner, Yvonne Heubach, Manuel Ruff, Hella Kohlhof, Stefan Strobl, Barbara Mayer, Michael Pawlak, Markus F. Templin, and Andreas Zell. RPPApipe: A pipeline for the analysis of reverse-phase protein array data. BioSystems, June 2014. [ DOI | details | link | pdf ]
[2] Johannes Eichner, Florian Topf, Andreas Dräger, Clemens Wrzodek, Dierk Wanke, and Andreas Zell. TFpredict and SABINE: Sequence-Based Prediction of Structural and Functional Characteristics of Transcription Factors. PLoS ONE, 8(12):e82238, December 2013. [ DOI | details | link | link ]
[3] Clemens Wrzodek. Inference and integration of biochemical networks with multilayered omics data. PhD thesis, University of Tuebingen, Tübingen, Germany, June 2013. [ details | link ]
[4] Adrian Schröder. Inference of gene-regulatory networks in primary human hepatocytes. PhD thesis, University of Tuebingen, Tübingen, Germany, November 2011. [ details | link ]
[5] Andreas Dräger, Nicolas Rodriguez, Marine Dumousseau, Alexander Dörr, Clemens Wrzodek, Nicolas Le Novère, Andreas Zell, and Michael Hucka. JSBML: a flexible Java library for working with SBML. Bioinformatics, 27(15):2167--2168, June 2011. [ DOI | details | link | pdf ]
[6] Clemens Wrzodek, Andreas Dräger, and Andreas Zell. KEGGtranslator: visualizing and converting the KEGG PATHWAY database to various formats. Bioinformatics, 27(16):2314--2315, June 2011. [ DOI | details | link | pdf ]
[7] Andreas Dräger. Computational Modeling of Biochemical Networks. PhD thesis, University of Tuebingen, Tübingen, Germany, January 2011. [ details | link ]
[8] Andreas Dräger, Hannes Planatscher, Dieudonné Motsou Wouamba, Adrian Schröder, Michael Hucka, Lukas Endler, Martin Golebiewski, Wolfgang Müller, and Andreas Zell. SBML2LATEX: Conversion of SBML files into human-readable reports. Bioinformatics, 25(11):1455--1456, April 2009. [ DOI | details | link | pdf ]

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