Cancer remains the leading cause of disease-related death in children after the first year of life. For the ~25% of children who experience relapses of their solid tumours, usually after intensive first-line therapy, curative treatment options are scarce. Preclinical drug testing to identify promising treatment options that match tumour biology is hampered by the facts that i) molecular genetic data on paediatric solid tumours from relapsed patients and thus our understanding of tumour evolution and therapy resistance are very limited and ii) for many of the high-risk entities, no appropriate and molecularly well characterized patient-derived models and/or genetic mouse models are available. Thus, quality-assured upfront preclinical testing of novel molecularly matching compounds in a (saturated) repertoire of well-characterized models will establish the basis to increase therapeutic successes of these drugs in children with solid malignancies. Since these tumours 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 the significant preclinical gap in identifying promising molecules to fight paediatric cancer, the main objectives for this preclinical platform project were to:
• Establish a representative collection of patient-derived in vitro and in vivo models (~400) as well as genetic mouse models of the most common paediatric solid high-risk entities and liquid tumours, including AML, ALL and Burkitt’s lymphoma including a significant proportion of models from relapses.
• Molecularly characterize and to quality-assess the models as well as the matching primary tumour samples and germline controls with state-of-the-art molecular diagnostic tools.
• enable regulatory filings in the EU and outside through the development of comprehensive preclinical data packages necessary to move drugs into clinical trials for children with cancer.
• Prioritize paediatric drug development using existing collections of molecular data for systematic target reports, followed by in vivo drug testing in faithful disease models. In vivo drug testing also included at least three standards-of care regimens for all models.
• Build an international consensus on preclinical data packages for paediatric cancer to enable clinical development.
• Identify suitable biomarkers for future clinical stratification.
Ultimately, the establishment of the sustainable and commercially viable ITCC-P4 has helped overcome a long-standing gap by enabling thorough molecular characterization of high-risk paediatric malignancies coupled with standardized preclinical testing procedures and is now anticipated to greatly expedite the development of more precise and efficacious drugs.
