Overview

Cancer remains the leading cause of disease-related death in children. For the ~25% of children who experience relapses of their malignant tumors, usually after very intensive first-line therapy, curative treatment options are scarce. Preclinical drug testing to identify promising treatment options that match the molecular make-up of the tumor is hampered by the fact that i) molecular genetic data on pediatric tumors from relapsed patients and thus our understanding of tumor evolution and therapy resistance are very limited to date and ii) for many of the high-risk entities, no appropriate and molecularly well characterized patient-derived models and/or genetic mouse models are currently available. Thus, quality-assured upfront preclinical testing of novel molecularly targeted compounds in a (saturated) repertoire of well-characterized models will establish the basis to increase therapeutic successes of these drugs in children with malignancies. Since these tumors are overall genetically much less complex than their adult counterparts, it is anticipated that it will be easier to identify powerful predictive biomarkers to allow for accurate matching of targets and drugs.

To address this high but as yet unmet clinical need, the main objectives for this preclinical platform project are the following:

• To establish a representative collection of patient-derived in vitro and in vivo models (target: n=420) as well as genetic mouse models (target: maximum of 15 spread out across multiple tumor types) of the most common pediatric high-risk entities including a significant proportion of models from relapses.
• To molecularly characterize and to quality-assess the models as well as the matching primary tumor samples and germline controls with state-of-the-art molecular diagnostic tools.
• To enable regulatory filings in the EU through the development of comprehensive preclinical data packages necessary to move drugs into clinical trials for children with tumors.
• To prioritize pediatric drug development using existing collections of molecular data for systematic target reports, followed by in vivo drug testing in faithful disease models including pharmacokinetics and pharmacodynamicswhere necessary (e.g., brain penetration). In vivo drug testing will also include at least three standard-of care-drugs for all models as a baseline for comparisons.
• To identify suitable biomarkers for future clinical stratification of patients across entities.
• Ultimately, the establishment of the ITCC-P4 platform over the long term will overcome a long-standing gap by enabling thorough molecular characterization of high-risk pediatric malignancies coupled with standardized preclinical testing procedures, and will thus greatly expedite the development of more precise and efficacious drugs for this patient group. Developing this platform as a public-private partnership will create a model for collaboration that can hopefully be extended to other types of cancer entities and patient groups.