Molecular Biology of Solid Tumours
Prof. Heinrich Kovar, PhD
The study of Ewing Sarcoma, a highly malignant bone-tumour in children and adolescents.
The Molecular Biology Group focuses predominantly on basic research with the aim of translating clinical observations into molecular patterns, and molecular patterns into diagnostic/prognostic tools and novel treatment options. For many years, our research has focused on Ewing sarcoma. There is an urgent need for new treatment options for this very malignant form of bone cancer in children and adolescents. Due to its relatively simple genetic makeup, this disease is particularly open to further research.
The search for the right medication.
The central genetic aberration of Ewing sarcoma is a fusion between the Ewing sarcoma gene EWS and the ETS oncogene FLI1 that results in the production of an aberrant gene regulatory protein, EWS-FLI1. Thus, the study of Ewing sarcoma also serves as a seminal example for ETS oncogene-driven oncogenesis in human cancer. The overall aim of our research is to identify druggable vulnerabilities in the molecular pathways that drive Ewing sarcoma pathogenesis. Since transcription factors - such as EWS-FLI1 – have thus far represented rather inaccessible therapeutic targets, we want to decode the molecules and biochemical pathways, which are active up- and downstream of EWS-FLI1 and are modulating EWS-FLI1 expression and its effects. We are approaching this goal through a multidisciplinary systems approach (European Framework 7 program funded project “ASSET”) using experimental perturbation in Ewing sarcoma cell lines, in-silico prediction and validation in primary tumour samples.
Studies of gene regulatory networks of the protein EWS-FLI1.
Our research focusses on the gene regulatory networks of EWS-FLI1. We use pangenomic screening approaches (mRNA, microRNA, transcription factor binding and epigenetic profiling by array technologies and high-throughput sequencing) to generate hypotheses about mechanisms of altered gene regulation in Ewing sarcoma. These are subsequently tested by targeted pathway perturbations using genetic (RNA interference, ectopic overexpression and targeted mutagenesis of genes of interest) and chemical (small molecule inhibitors) tools. We also investigate the influence of the microenvironment (e.g. hypoxia, immune cells) on the EWS-FLI1 gene regulatory network in vitro, and study characteristics associated with malignancy and metastasis formation in European (ERA-NET project PROVABES; FP7 project ASSET) and internationally funded (Liddy Shriver Sarcoma initiative) collaborative projects. Finally, we engage in Europe-wide clinical Ewing sarcoma trials (Euro Ewing 99, Ewing 2008; European Ewing Sarcoma Consortium) to prospectively test the potential prognostic utility of EWS-FLI1 and its downstream effectors in terms of the course of the disease and according treatments  .
Bilke S, Schwentner R, Yang F, Kauer MO, Jug G, Walker RL, Davis S, Zhu YJ, Pineda M, Meltzer PS, Kovar H. (2013). Oncogenic ETS fusions deregulate E2F3 target genes in Ewing sarcoma and prostate cancer. Genome Res. 2013 Aug 12. [Epub ahead of print]
Niedan S, Kauer M, Aryee DN, Kofler R, Schwentner R, Meier A, Pötschger U, Kontny U, Kovar H. (2013). Suppression of FOXO1 is responsible for a growth regulatory repressive transcriptional sub-signature of EWS-FLI1 in Ewing sarcoma. Oncogene. 2013 Sep 2. doi: 10.1038/onc.2013.361. [Epub ahead of print]
Le Deley M-C, Delattre O, Schäfer K-L, Burchill SA, Köhler G, Hogendoorn PCW, Lion T, Poremba C, Marandet J, Ballet S, Pierron G, Brownhill SC, Nesslböck M, Ranft A, Dirksen U, Oberlin O, Lewis IJ, Craft AW, Jürgens H, Kovar H. (2010) Impact of EWS-ETS fusion type on disease progression in Ewing´s sarcoma / peripheral primitive neuroectodermal tumor: prospective results from the cooperative Euro-E.W.I.N.G.99 trial. J. Clin. Oncol. 28(12):1982-8.
Kauer M, Ban J, Kofler R, Walker B, Davis S, Meltzer P, Kovar H. (2009) A molecular function map of Ewing's sarcoma. PLoS ONE 4:e5415
Ban J, Bennani-Baiti I, Kauer M, Schaefer K-L, Poremba C, Jug G, Schwentner R, Smrzka O, Muehlbacher K, Aryee D, Kovar H. (2008) EWS-FLI1 suppresses NOTCH-activated p53 in Ewing´s sarcoma. Cancer Res. 68, 7100-9.