Schäfer
Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Onkologie, Abteilung » Prof. Dr. Felix Niggli » Schäfer
Completed research project
| Title / Titel | Oncogenic fusion proteins as therapeutic targets in pediatric sarcomas | ||
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| Abstract (PDF, 14 KB) | |||
| Summary / Zusammenfassung | Sarcomas account for some of the most aggressive childhood cancers with high metastatic potential. Among them are Ewing’s sarcoma (ES) and alveolar Rhabdomysarcoma (aRMS) as the more frequent dieseases. Although optimization of current treatment regimens in general has significantly advanced prognosis of cancer patients until today, there is an urgent need to identify and develop alternative treatment strategies to improve therapy against chemoresistant tumors as well as to minimize treatment related side effects, an issue especially important for childhood long term survivors. However, because pediatric malignancies are rare, they are not an industry priority for drug development. Both ES and aRMS are characterized by the expression of tumor-specific chimaeric transcription factors, namely EWS/FLI1 and PAX3/FKHR, respectively. Survival of such translocation-positive cancer cells is dependent on continuous expression of the fusion protein, as both downregulation or inhibition induces apoptosis both in vitro as well as in vivo. Therefore, due to their malignant cell specificity the tumor-specific chimaeric transcription factors represent attractive therapeutic targets. However, until now these targets have been largely ignored because they are, as transcriptional regulators, generally considered “undruggable”. We hypothesize that small molecular drugs might already exist for the treatment of these sarcomas, but strategies to prioritize them have been lacking. We propose therefore to identify small molecules capable to specifically modulate the transcriptional activity of chimaeric oncogenic transcription factors in sarcomas. Pre-clinical evaluation of identified molecules will be carried out in different tumor models in vivo. Alternatively, we will screen an siRNA library to identify relevant biological pathway that can interfere with the transcriptional activity of EWS/FLI1 and PAX3/FKHR |
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| Publications / Publikationen | Amstutz RA, WachtelM, Troxler H, Kleinert P, Ebauer M, Oehler C, Fabbro D, Niggli FK and Schäfer BW (2008) Specific phosphorylation events regulate transcriptional activity of PAX3/FKHR and reveal novel therapeutic possibilities, Cancer Research 68, 3767-3776.Ebauer M, Wachtel M, Niggli FK, Schäfer BW (2007) Comparative expression profiling identifiesTFAP2beta as an essential in vivo target of PAX3/FKHR. Oncogene, 26, 7267-7281.Wachtel M, Runge T, Leuschner I, Koscielniak E, Stegmaier S, Treuner J, Odermatt B, Behnke S, Niggli FK, Schäfer BW (2006) Subtype and prognostic classification of rhabdomyosarcoma by immunohistochemistry, J Clin Oncology, 24, 816-822. | ||
| Keywords / Suchbegriffe | Rhabdomyosarcoma, Ewing's Sarcoma, chromosomal translocations, oncogenic transcription factors, small molecule chemical library, siRNA screen, sarcoma tumor bank | ||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Other links to external web pages | http://www.kispi.uzh.ch/onkologie | ||
| Funding source(s) / Unterstützt durch |
SNF (Personen- und Projektförderung), Foundation OncoSuisse, Krebsliga Kt. Zürich |
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| Duration of Project / Projektdauer | Oct 2008 to Dec 2010 |