Work package leader:

Marcel Kool (DKFZ) and David Shields (Pfizer)
Co-leaders: Johannes H. Schulte (Charite), Gudrun Schleiermacher (IC), Sara Colombetti (Roche), Jan-Henning Klusmann (MLU), Christina Guttke (Janssen)

Objectives of the work package:

Pediatric cancer model development and characterization

Description of the tasks:

One of the central activities of the consortium is the development of representative and robust preclinical models accurately reflecting human disease and providing efficient platforms for in vivo functional compound testing (WP5). Prominent to WP3 is the development of a sustainable infrastructure for generation and use of Patient-Derived Models (PDMs) (Patient-Derived Xenograft (PDX) and organoid models) and Genetically Engineered Mouse Models (GEMMs). Robust genomic characterization of all established models will be conducted, including cross-species human (primary/PDX/organoid): mouse (GEMM) comparisons. Several specialized academic labs, SMEs (EPO, XenTech) and EFPIA partners (Charles River) will generate up to 420 PDX models, representing the major paediatric solid and liquid tumor entities.
To more faithfully replicate the biology of the brain tumors, orthotopic (intracranial) engraftment will be conducted using stereotactic injections of patient-derived or GEMM-derived tumor material. For all other solid tumors, flank engraftment will be performed. For the leukemiasorthotopic (in case of leukaemias bone marrow) engraftment will be conducted. To assess the predictive power of therapeutic testing studies using ex vivo organoid or PDX cultures, a proof-of-concept panel of 40 organoid lines from solid tumors and 25 leukemic PDX, representing up to five tumor types will be established at PMC, Newcastle and Zuerich.

A comprehensive molecular characterization of all primary tumor material, matching germline samples, derived models and GEMMs will be performed to enable full interpretation of any preclinical results. This will be done at the DKFZ, Institut Curie and PMC. The comprehensive molecular characterization will include high-coverage, whole-exome and low-coverage, whole-genome sequencing of all PDMs and their matching primary tumors and germline DNA, as well as RNAseq, Affymetrix gene expression profiling and DNA methylation profiling.