B6: Multi-targeting and identification of synergistic activities to overcome therapy resistance in ALL

The Pediatric Leukemia Group has established a NOD/SCID/hu-ALL pre-clinical xenograft model for pediatric ALL with a large biobank of individual patient-derived primografts. Using this model system, efficacy of single agents interfering with cellular signaling or cell death, and resistance mechanisms upon directed therapy have been evaluated in the ongoing period. Since effective, targeted anti-leukemia treatment will require combination therapies, one focus will be now to characterize cooperative activities of combinatorial approaches in patient-derived xenograft samples in a large-scale approach. Combinations showing synergistic anti-ALL activity will be further evaluated in a phase II-like study in this preclinical ALL model. In addition, relapse-derived and genetically modified leukemias with defined disturbed apoptosis signaling will be studied in order to identify specific pharmaco-profiles overcoming resistance. This also provides a further basis for the implementation of targeting survival pathways and cell death inducers/modifiers (BH3-mimetics, SMAC-mimetics) into therapy of pediatric ALL. These studies may also impact on immunotherapy approaches such as CAR-T cells and BITEs.

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