Project Summary – Overall The overarching goal of this Patient Derived Xenograft (PDX) Development and Trial Center (T-PDTC) is to develop functional precision combination therapies that can be translated into clinical trials to overcome drug resistance and produce to long-term responses improving the outcomes of melanoma patients. The melanoma treatment landscape has radically improved in the past decade due to availability of new immune- and targeted- therapies available. Targeted therapies using BRAF and MEK inhibitors have been approved for patients with BRAFV600E/K mutations, which are present in ~50% of cutaneous melanomas. These treatments elicit clinical responses in ~80% of BRAFV600 mutant patients. However, most patients eventually progress. Additionally, there are no effective targeted therapies for patients whose tumors harbor wild-type BRAF. Thus, there is an urgent unmet clinical need to develop efficacious treatments to prevent or overcome resistance to current FDA- approved therapies. To facilitate the development of new therapeutic strategies that can be translated into clinical trials, we have developed a broad collection of PDX models that reflects the clinical, histological, and genetic heterogeneity of melanoma. Our collection of >500 PDX models represents one of the largest collections for any human malignancy. Our initial studies have demonstrated that our PDX collection recapitulates the molecular heterogeneity observed in patients. This collection also includes a subset of PDX established from patients with intrinsic and acquired resistance to targeted- and immune-therapies and rare melanoma subtypes. These efforts have generated a robust pre-clinical resource to develop, refine, and prioritize new functional precision combinatorial therapies for melanoma patients. This T-PDTC constitutes a multi-disciplinary and multi- institutional Program focused on the use and continued expansion of our melanoma PDX collection and organoids to identify new therapeutic combination approaches that will fill important clinical gaps. The Program consists of two research projects and three Cores from a team that has worked extremely well together over the last five years, publishing high-impact collaborative papers. The Research Projects are designed to develop functional precision combination therapies for the most challenging types of melanomas: those that are resistant to current therapies and tumors that lack BRAF-mutations (BRAFWT). We will map the molecular landscape of our melanoma PDXs and organoids by integrating DNA, RNA, and protein data to nominate combination therapies matching their molecular profile. We will develop and implement mechanism-based preclinical trials of drug combinations in our large set of molecularly characterized PDXs. To do this, we will focus on NCI- Investigational New Drug (IND) agents to advance melanoma precision therapy, while offsetting drug resistance and producing durable responses. We expect to ga...