Project: Optimizing First-line therapy for aggressive neuroblastoma by systems medicine strategies overcoming secindary drug resitance

Acronym	OPTIMIZE-NB (Reference Number: JTC1_93)
Duration	01/05/2016 - 01/08/2019
Project Topic	While most tumors respond to the initial therapy, the recurrence of the tumor and the evolution of therapy resistance remains a major medical problem. Current therapy schedules are shaped by the contingencies of their historical development and have not undergone rational optimization to effectively induce tumor cell apoptosis and cellular senescence, and thus prevent recurrence. The applicants ofOPTIMIZE-NB have previously collaborated in systems biology consortia on neuroblastoma - a genetically well characterized and often fatal malignancy of early childhood. The low genetic complexity of this and other pediatric cancers offers a unique chance to delineate and tackle core disease mechanisms with minimal noise from passenger mutations. Through combining single-cell-resolved in-vitro approaches withmathematical modeling, we have previously established that clonal regrowth of neuroblastoma after therapy is initiated from a small subpopulation of "resister" cells that form a subset of the tumor mass with recognizable molecular and functional properties. We have also shown in initial experiments that these properties could be exploited for the rational improvement of therapy. In this project, we aim tosystematically improve treatment schedules for the first-line therapy of aggressive NB by combining computational research, in vitro experiments on patient-derived NB cell lines and NB mouse models. To make a direct impact on the clinic, we will focus on treatment options that – when proven successful in these preclinical settings – can immediately enter clinical trials: (1) the temporal treatmentregimen and dosage of conventional combination chemotherapy of aggressive neuroblastome with 6 different drugs, and (2) the combination of chemotherapy with already approved targeted drugs with an ALK inhibitor as first proof-of-principle. Promising results of OPTIMIZE-NB will be translated into an improved design for the upcoming clinical phase III NB trial, NB-HR 2017.
Network	ERACoSysMed
Call	1st Call: European Research Projects to demonstrate the feasibility and benefits of systems medicine

Project partner

Number	Name	Role	Country
1	Deutsches Krebsforschungszentrum	Coordinator	Germany
2	Charité - Universitätsmedizin Berlin	Partner	Germany
3	Ghent University	Partner	Belgium
4	University of Amsterdam	Partner	Netherlands