Project: Informing treatment decisions of relapsed neuroblastomas by inference of tumor evolution

Acronym	INFER-NB (Reference Number: ID29)
Duration	01/06/2020 - 30/11/2023
Project Topic	The comprehensive characterization of cancer (epi-)genomes has identified numerous genetic lesions associated with diverse clinical phenotypes. The development of new drugs targeting these lesions raised hopes for precise therapy. Thus far, however, sustained tumor regression upon molecularly targeted therapies has been rare. Current research therefore focuses on the mechanistic understanding of tumor heterogeneity, elucidating how cancer drivers reshape cell physiology in specific cell contexts and drive tumor evolution. In INFER-NB, we will bring our published computational models for dissecting tumor heterogeneity and clonal evolution to clinical application. We will elucidate the evolution of individual tumors prior to and under therapy, and leverage these insights to design therapeutic strategies that effectively target clonally heterogeneous tumors of different developmental origins. We bring together a unique clinical data set by connecting three ongoing sequencing studies of relapsed pediatric cancers in France, the Netherlands and Germany (MAPPYACTS, iTHER, INFORM). Our focus will be on the common pediatric cancer, neuroblastoma, which derives from diverse progenitor cells of the sympathetic nervous system and where treatment success of high-risk cases remains low. Most patients with primary high-risk NB in Europe are treated within one of two clinical trials, SIOPEN (NCT01704716) or GPOH-NB2004-HR (NCT00526318), and clonal evolution under therapy will be compared for these two first-line treatments. Relapsed patients enrolled in MAPPYACTS/iTHER/INFORM were treated with molecularly targeted therapies (ALKi, CDK4/6i, RASi) within biomarker-driven trials (Pediatric MATCH, ESMART, INFORM2) and re-sequenced upon second or third relapse, allowing us now to infer clonal evolution upon molecularly targeted therapies. We expect that identifying developmental origin and clonal evolution of individual tumors will enable more precise and effective targeted treatment.
Network	ERACoSysMed
Call	3rd Joint Transnational Call for European Research Projects on Systems Medicine

Project partner

Number	Name	Role	Country
1	German Cancer Research Center	Coordinator	Germany
2	Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ)	Partner	Germany
3	Princes Maxima Center for Pediatric Oncology	Partner	Netherlands
4	Institut Curie	Partner	France
5	Academic Medical Center (AMC)	Partner	Netherlands