banda transcan 2 2016ul

Title: Harnessing BRCAness as a therapeutic target in high-risk pediatric solid tumors

Project Coordinator:
Stefan Michael Pfister (Germany), German Cancer Research Center Heidelberg (DKFZ) and Hopp Children´s Cancer Center at the NCT Heidelberg (KiTZ)

Project Partners:
Didier Surdez, (France), Institut Curie, INSERM U830 and SIREDO center (Soins, Innovation, Recherche, en oncologie de l’Enfant, del’aDOlescent et de l’adulte jeune), Paris 
Birgit Geoerger (France), Institut Gustave Roussy, UMR 8203 CNRS and Department of Pediatric and Adolescent Oncology, Villejuif 
Jan Molenaar, (Netherlands), Prinses Máxima Centrum voor Kinderoncologie Dept of Translational Research, Utrecht
Johannes Gojo (Austria), Medical University of Vienna, Department of Pediatrics and Adolescent Medicine and Institute of Cancer Research, Vienna
Massimo Serra (Italy), Instituto Ortopedico Rizzoli, IOR, Laboratory of Experimental Oncology, Bologna.
Johannes Schulte (Germany), Charité Universitätsmedizin Berlin Campus Virchow-Klinikum, Otto-Heubner-Centrum f. Kinder- u. Jugendmedizin Klinik für Pädiatrie m.S. Onkologie/Hämatologie/SZT, Berlin

Project Abstract:
Despite a concerted European effort to widely apply next-generation molecular diagnostics, cure rates for pediatric solid tumors at relapse remain dismal. Approximately 50% of cases do not have an obvious genetic drug target. Our recent pediatric pan-cancer study (www.pedpancan.com) suggests that a large proportion of Ewing sarcoma, osteosarcoma, glioblastoma, medulloblastoma, neuroblastoma and rhabdomyosarcoma, all of which are entities of high medical need, show a mutational signature compatible with BRCAness, implicating sensitivity to PARP inhibition. We hypothesize that a fraction of pediatric solid tumors with a BRCAness mutational signature will be sensitive to PARP inhibition. 
We aim to (i) assess the sensitivity of BRCAness positive tumors (and negative controls) to combinations of PARP inhibitors and DNA-damaging chemotherapy in vivo and (ii) tune our BCRAness calling algorithm by using preclinical in vivo response data for its first clinical application. As secondary aims, we strive to understand the “degree of BRCAness” necessary to sensitize for PARP inhibition, the underlying genetic causes, resistance mechanisms, and the predictivity of in vitro testing. The preclinical phase II trial “BRCAddict” will be performed in an n=1 fashion with 10 different PDX models from six different entities in each treatment arm. BCRAness will be assessed by whole-genome and transcriptome sequencing of the models using an established bioinformatic algorithm. We expect 30-80% of BRCAness positive cases in the entities of interest. In vitro testing of the same combinations will be performed in a cell line panel and drug responses will be compared with in vivo data.
The results of this preclinical trial and the accompanying biomarker evaluation will lay the groundwork for a molecularly stratified phase II study across pediatric solid tumors within the European Innovative Therapies for Children with Cancer (ITCC) network, in which all applicants are involved.

 

(Project funded under JTC 2017)


TRANSCAN-2 News


A new TRANSCAN-2 brochure, highlighting key achievements, is available for download

The 3rd and final TRANSCAN-2 symposium on Tumour Heterogeneity was held in Milan on October 24th
The symposium included talks from the funded consortia of JTC2014, co-funded by the EU (see the abstract book), an exciting discussion on the impact and added value of transnational collaborations on cancer research and a poster prize competition for young scientists.
The event was hosted by Regione Lombardia, Italy with the collaboration of Fondazione Regionale per la Ricerca Biomedica
 
For further information please contact: liron.ef@moh.gov.il

 

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eu flagship

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 643638.

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