CORE C ABSTRACT Patient-derived Xenograft (PDX) and Syngeneic Mouse Melanoma Core services. Despite recent development of targeted therapies and immunotherapies for metastatic human melanoma, innate, adaptive and acquired resistance arise and limit clinical survival benefits. This core will subserve the overarching goals and specific aims of each of the three Projects in this PPG. Defining resistance mechanisms in an in vitro system is an important first step but is limited in its capacity to recapitulate inter- and intra-tumor heterogeneity and incapable of reproducing immune and stromal environmental impacts. The development of Patient-derived Xenograft (PDX) models that maintain the characteristics of the patient's tumor will ensure clinical and in vivo relevance of proposed studies in each Project in this PPG. The PDX and murine melanoma core aims to perform a prospective collection of tumor biopsies in order to create an extensive library of fully characterized PDX models. The core will provide access to a biobank of PDX models that have been developed from biopsy samples provided by the Core B and from outside collaborators as well as murine melanoma models representing the genomic diversity of metastatic human melanoma. It will also generate models of acquired resistance to currently FDA-approved or clinically-tested targeted therapies and key combinations proposed in this PPG. We will also generate cell lines from PDX models to enable investigators of the Projects to perform first-level mechanistic analyses. Finally, the core will generate a suite of temporal/spatial multi-omic data that can be mined by each of the Projects to identifiy specific models that would be initially used as proof-of- concepts and later to assemble panels with sufficient diversity to evaluate reproducibility or biologic effects restricted to certain genomic, epigenomic or immunologic contexts.
Patient-derived Xenograft (PDX) and Syngeneic Mouse Melanoma Core The study of therapeutic resistance in melanoma requires experimental models which faithfully recapitulate the complexity and heterogeneity of the disease. This proposed PDX and murine melanoma core will provide the three Projects in this application and the melanoma scientific community with a large-scale library of Patient- derived Xenograft (PDX) and murine melanoma models encompassing the genomic diversity of human melanomas. Through next generation omic profiling of these models, investigators will be able to discover or validate novel strategies to overcome resistance in the best possible melanoma model.
