ABSTRACT With recent enactment of the Research to Accelerate Cures and Equity (RACE) for Children Act, there is a growing impetus to identify pediatric indications for molecularly targeted drugs. Accordingly, there is a pressing need for clinically relevant preclinical studies that can help prioritize pediatric indications for clinical application of nearly the entire universe of cancer drugs currently in development. To meet this need, we established a preclinical testing program that has created >300 genomically-characterized pediatric solid tumor patient- derived xenograft (PDX) models between the pediatric oncology programs at Memorial Sloan Kettering Cancer Center and University of California San Francisco. We propose to leverage this large portfolio of models across a diversity of diseases, along with the deep expertise of the team, to establish a NCI Pediatric In Vivo Testing Program (Ped-In Vivo-TP) Research Team focused on pediatric bone and soft tissue sarcomas, renal tumors, desmoplastic small round cell tumor (DSRCT) and other rare pediatric solid tumors. The Aims of this Research Team are: Aim 1. Integrate with the Coordinating Center and other Research Teams to prioritize agents for preclinical evaluation. We will leverage our team's translational expertise as well as existing connections to disease committees within cooperative groups to inform and facilitate new agent selection and preclinical evaluation in appropriate models to prioritize agents to advance into pediatric oncology clinical trials. Aim 2. Utilize PDX portfolios representative of disease heterogeneity to assess therapeutic agents. We will utilize the >300 PDX models from MSKCC and UCSF, supplemented with models from the PROXC consortium where necessary, to assess 8-10 therapeutic agents/year using study designs matched to the therapeutic question. All preclinical drug testing will be conducted at MSKCC. Aim 3. Align central and local data analyses to ensure rigor in results reporting. For the purposes of prioritization, we will maintain equipoise in validating (“go”) or invalidating (“no go”) therapeutic hypotheses, and will complement central data analyses with advanced local biostatistical expertise. Aim 4. Translational biomarker discovery. We will leverage the combined expertise of our Research Team to identify clinically translatable biomarkers predictive of enhanced response or drug resistance. In some cases, predictive biomarkers may not be genetic, but instead will depend on transcriptional or protein-based assays of target activity. In other cases, genomically identified biomarkers have to be translated to clinically utilizable assays. Together, the expertise and capabilities of this Research Team will support the rigorous evaluation of novel therapeutic hypotheses in clinically-representative models to enable prioritization and translation of the most promising emerging agents into biomarker-informed clinical trials for children with high risk solid tumors...