Project Summary Children with disseminated neuroblastoma have a very high risk of treatment failure and death despite receiving intensified chemotherapy, radiation therapy and immunotherapy. The long-term goal of the Mossé and Maris translational research programs is to substantively improve neuroblastoma cure rates by developing patient-specific therapies that target the unique oncogenic drivers of each case. Within the context of the National Cancer Institute’s Pediatric In Vivo Testing Program (Ped-In Vivo-TP) we propose a Neuroblastoma Research Program built on richly annotated and highly characterized patient derived xenograft (PDX) and other recently developed murine models of this disease. The central hypothesis to be tested in this Program is that neuroblastoma-specific oncogenic drivers and optimal immunotherapeutic targets can be defined and exploited through rationally designed therapies based on validated and clinically measurable biomarkers. Through our dedicated focus on neuroblastoma and our central role in the former Pediatric Preclinical Testing Program and Consortium, we have developed an investigative team and rich set of resources and reagents to be uniquely positioned to achieve the goals of the Ped-In Vivo-TP. Here we propose to use a large (and growing) collection of PDX models that have been fully characterized with the most modern genomic technologies to address the challenge of prioritizing the large armamentarium of anti-cancer agents in development so that early phase biomarker-driven clinical trials can be designed with the objective of showing potent and specific anti-tumor activity. We propose three specific aims directed towards 1) developing and characterizing highly annotated models of human neuroblastoma; 2) performing preclinical trials with drugs directed against defined therapeutic vulnerabilities in order to prioritize agents for the clinic, and 3) developing the portfolio of preclinical data required for design of clinical trials with robust biomarkers for patient selection and monitoring. In collaboration with other preclinical testing programs, we will seek to determine if discoveries in our program are relevant to other childhood cancers and collaborate across disease groups on clinical development strategies. Thus, this Program will seek to shift the paradigm for how high-risk neuroblastoma patients are treated with the goal of substantively improving the outcomes, both in terms of cure rates, but also by decreasing the toxicity associated with current standards of care.