EU-IMI MARCAR - bioMARkers and molecular tumor classification for non-genotoxic CARcinogenesis
MARCAR Logo

Funding: This collaborative EU project is funded by the "Innovative Medicines Initiative (IMI)".

 

Abstract: MARCAR aims to establish reliable early markers and molecular classification of tumors in non-genotoxic carcinogenesis, applying a mechanism-based approach. Benefits are improved drug safety, more efficient drug development, and progress with 3 R issues. MARCAR focuses on rodent liver, the major target organ of non-genotoxic carcinogens (NGC). However, this approach will facilitate predictions for other organs. Innovative industry-relevant experimental models will be developed: (i) Transgenic mice nulled or humanized for NGC-responsive nuclear receptors, (ii) transgenic mice excreting marker proteins in urine, including oxidative stress reporter mice to monitor ROS production, (iii) transgenic mice allowing in vivo bioimaging of preneoplastic lesions (PNL) and tumors, and (iv) primary cultures of human/rodent hepatocytes and their co-cultivation with mesenchymal cells which modulate carcinogenesis by NGC. In these systems, novel molecular technologies will be used for profiling the genome, epigenome, transcriptome and proteome/phosphoproteome to provide global molecular signatures of NGC-induced signalling. These complementary technologies in conjunction with standardized data management and advanced marker identification algorithms will lead to molecular classification of tumors and PNL, and identify predictive molecular signatures of spontaneous vs drug induced tumors. Biomarker panels indicating the mechanisms of NGC action will be derived and translated into assay systems. The validity, predictivity and robustness of biomarkers will be tested in collaboration with EFPIA, employing well-characterized pre-clinical models. For clinical translation humanized/human systems and materials from clinical trials will be tested for NGC effects on homologues of rodent biomarkers. The provision of high-quality deliverables is facilitated by complementary expertise in carcinogenesis/bioanalysis, in conjunction with know-how and in kind contributions of EFPIA partners.

Collaborators:

Organisation name

Country

Novartis Institutes for BioMedical Research

Switzerland

University of Dundee

United Kingdom

CXR Biosciences Limited

United Kingdom

Medizinische Universitaet Wien

Austria

Medical Research Council UK

United Kingdom

Eberhard-Karls-Universitaet Tuebingen (Prof. Schwarz)

Germany

Eberhard-Karls-Universitaet Tuebingen (Prof. Zell)

Germany

Eberhard-Karls-Universitaet Tuebingen (Prof. Pichler)

Germany

NMI Natural and Medical Sciences Institute at the University of Tuebingen

Germany

Inserm

France

Solvay

International

Boehringer Ingelheim

Germany

Bayer Healthcare

International

UCB Group

Belgium

Lundbeck

Denmark

 

Official Homepage: http://www.imi-marcar.eu/


Contact: Michael Römer

Publications

[1] Michael Römer, Heidrun Ellinger-Ziegelbauer, Bettina Grasl-Kraupp, Michael Schwarz, and Andreas Zell. MARCARviz: Interactive web-platform for exploratory analysis of toxicogenomics data for nongenotoxic hepatocarcinogenesis. PeerJ Preprints, 4:e2393v1, August 2016. [ DOI ]
[2] Albert Braeuning, Alina Gavrilov, Miriam Geissler, Christine Wenz, Sabine Colnot, Markus F Templin, Ute Metzger, Michael Römer, Andreas Zell, and Michael Schwarz. Tumor promotion and inhibition by phenobarbital in livers of conditional apc-deficient mice. Archives of Toxicology, pages 1-14, February 2016.
[3] Michael Römer, Johannes Eichner, Andreas Dräger, Clemens Wrzodek, Finja Wrzodek, and Andreas Zell. ZBIT Bioinformatics Toolbox: a Web-Platform for Systems Biology and Expression Data Analysis. PLoS ONE, 11(2):e0149263, February 2016. [ DOI | details | link ]
[4] Bettina Grasl-Kraupp, Teresa Riegler, Marzieh Nejabat, Jakob Paur, Johannes Eichner, Michael Römer, Andreas Zell, Rolf Schulte-Hermann, and Wolfgang Huber. Abstract 810: Non-genotoxic hepatocarcinogens induce growth and anti-apoptotic pathways in hepatocytes via mesenchymal cytokines. Cancer Research, 75(15 Supplement):810, April 2015. [ DOI | link ]
[5] Michael Römer, Linus Backert, Johannes Eichner, and Andreas Zell. Toxdbscan: Large-scale similarity screening of toxicological databases for drug candidates. International Journal of Molecular Sciences, 15(10):19037-19055, October 2014. [ DOI | link ]
[6] 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 ]
[7] Johannes Eichner, Lars Rosenbaum, Clemens Wrzodek, Hans-Ulrich Häring, Andreas Zell, and Rainer Lehmann. Integrated enrichment analysis and pathway-centered visualization of metabolomics, proteomics, transcriptomics, and genomics data by using the InCroMAP software. Journal of Chromatography B, May 2014. [ DOI | link ]
[8] Johannes Eichner, Clemens Wrzodek, Michael Römer, Heidrun Ellinger-Ziegelbauer, and Andreas Zell. Evaluation of toxicogenomics approaches for assessing the risk of nongenotoxic carcinogenicity in rat liver. PLoS ONE, 9(5):e97678, May 2014. [ DOI | link ]
[9] Michael Römer, Johannes Eichner, Ute Metzger, Markus F. Templin, Simon Plummer, Heidrun Ellinger-Ziegelbauer, and Andreas Zell. Cross-platform toxicogenomics for the prediction of non-genotoxic hepatocarcinogenesis in rat. PLoS ONE, 9(5):e97640, May 2014. [ DOI | link ]
[10] Elif B. Unterberger, Johannes Eichner, Clemens Wrzodek, Harri Lempiäinen, Raphaëlle Luisier, Rémi Terranova, Ute Metzger, Simon Plummer, Thomas Knorpp, Albert Braeuning, Jonathan Moggs, Markus Templin, Valerie Honndorf, Martial Piotto, Andreas Zell, and Michael Schwarz. Metabolic Programs Orchestrated by the Activated Ha-ras and β-Catenin Oncoproteins in Mouse Liver Tumors. International Journal of Cancer, March 2014. [ DOI | link ]
[11] Johannes Eichner, Nadine Kossler, Clemens Wrzodek, Arno Kalkuhl, Dorthe Bach Toft, Nina Ostenfeldt, Virgile Richard, and Andreas Zell. A Toxicogenomic Approach for the Prediction of Murine Hepatocarcinogenesis Using Ensemble Feature Selection. PLoS ONE, 8(9):e73938, September 2013. [ DOI | link ]
[12] Clemens Wrzodek. Inference and integration of biochemical networks with multilayered omics data. PhD thesis, University of Tuebingen, Tübingen, Germany, June 2013. [ details | link ]
[13] Clemens Wrzodek, Johannes Eichner, Finja Büchel, and Andreas Zell. InCroMAP: Integrated analysis of Cross-platform MicroArray and Pathway data. Bioinformatics, 29(4):506-508, December 2012. [ DOI | arXiv | details | link | pdf ]
[14] Harri Lempiäinen, Philippe Couttet, Federico Bolognani, Arne Müller, Valérie Dubost, Raphaëlle Luisier, Espinola Alberto Del Rio, Veronique Vitry, Elif B Unterberger, John P Thomson, Fridolin Treindl, Ute Metzger, Clemens Wrzodek, Florian Hahne, Tulipan Zollinger, Sarah Brasa, Magdalena Kalteis, Magali Marcellin, Fanny Giudicelli, Albert Braeuning, Laurent Morawiec, Natasa Zamurovic, Ulrich Längle, Nico Scheer, Dirk Schübeler, Jay Goodman, Salah-Dine Chibout, Jennifer Marlowe, Diethilde Theil, David J Heard, Olivier Grenet, Andreas Zell, Markus F Templin, Richard R Meehan, C. Roland Wolf, Clifford R Elcombe, Michael Schwarz, Pierre Moulin, Rémi Terranova, and Jonathan G Moggs. Identification of Dlk1-Dio3 imprinted gene cluster non-coding RNAs as novel candidate biomarkers for liver tumor promotion. Toxicological Sciences, 131(2):375-386, October 2012. [ DOI | arXiv | details | link | pdf ]
[15] Clemens Wrzodek, Johannes Eichner, and Andreas Zell. Pathway-based visualization of cross-platform microarray datasets. Bioinformatics, 28(23):3021-3026, September 2012. [ DOI | arXiv | details | link | pdf ]
[16] Clemens Wrzodek, Finja Büchel, Georg Hinselmann, Johannes Eichner, Florian Mittag, and Andreas Zell. Linking the epigenome to the genome: Correlation of different features to DNA methylation of CpG islands. PLoS ONE, 7(4):e35327, 04 2012. [ DOI | details | link | pdf ]

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