PROJECT SUMMARY Patient-derived xenografts (PDXs) are a powerful model system to assess efficacy of anti-cancer agents and understand molecular mechanisms of drug resistance. By applying agent combinations against patient-derived models, it is possible to obtain evidence to determine the most promising combinations for advancement to clinical testing in defined sub-populations of cancer patients. However, integration of PDX drug response with molecular characterization data across diverse PDX collections is needed to enable this vision. A key aspect is the need for well-managed resources for community sharing and large-scale analysis of standardized datasets from PDXs and other patient-derived models. The Jackson Laboratory-Seven Bridges (JAX-SB) PDX Data Commons and Coordination Center (PDCCC) has addressed this challenge for the last 5 years, uniting the efforts of the data-generating (PDX Development and Trial Centers/PDTCs) and PDX model sharing (NCI’s Patient-Derived Model Repository/PDMR) components of the PDX Development and Trials Centers Research Network (PDXNet) into a cohesive, trans-Network whole. Using innovative cloud computing and bioinformatic approaches, our PDCCC provides administrative and computational infrastructure for PDXNet to enable PDX method standardization, model sharing, data sharing, and massive-scale data analysis. To date, we have built the PDXNet Portal, which currently contains PDXNet model information and data resources from 334 new models across 33 cancer types. Our PDCCC team has both facilitated and actively guided consortium collaborative projects, leading to several major publications and 10 Cancer Therapy Evaluation Program Letters of Intent. Here, we propose to enhance the PDXNet Portal and refine our organizational activities to address needs clarified by the NCI and PDX communities, including: faster translation of PDX studies to clinical trials; precise organization and sharing of multi-omic and treatment response data; and development of predictors of clinical treatment response. Our Specific Aims are: 1) To provide robust PDCCC support for PDXNet stakeholders through regular committees, personnel expertise, and project tools; 2) To enhance PDXNet Portal content, functionality, and data sharing; and 3) To develop and implement strategies that accelerate PDX translation to clinical trials. Through these Aims, we will coordinate the activities of the PDXNet to increase the value of patient-derived cancer model treatment studies and speed the generation of clinical trials.