ABSTRACT The long-term goal of the SPORE in Soft Tissue Sarcoma is to reduce the morbidity and mortality from soft tissue sarcoma by developing therapies targeted to specific molecular, genetic, epigenetic, and signaling pathway alterations or specific sarcoma type and subtype. To pursue this, we will focus our efforts on 4 broad translational research objectives: 1. Define shared and type-specific molecular mechanisms of sarcomagenesis to identify new rational therapeutic targets; 2. Define mechanisms of resistance to targeted and immune therapies; 3. Clinically validate new therapeutic targets and treatments in soft tissue sarcoma patients and facilitate the development, recruitment, and application of clinical trials that serve both the adult and pediatric populations; 4. Discover specific molecular alterations and new biomarkers that predict outcome and response to targeted and immune therapy. To achieve these goals, we have marshaled an integrated, multidisciplinary group of basic and clinical investigators, all armed with a unique resource, a clinicopathologic and outcomes database prospectively collected over a 41-year period. This database now contains data for over 14,990 patients treated for soft tissue sarcoma at MSK. The database is linked to an extensive sarcoma tissue and blood bank, which in turn is linked to an extensive multi-platform molecular genetic and epigenetic dataset and a collection of primary sarcoma cell lines and patient-derived xenograft (PDX) models of human sarcoma. The SPORE is structured around 3 research projects, 4 cores, and career enhancement and developmental research programs. Each research project focuses on two or more of the 4 broad translational research goals listed above. RP1 (GIST Pathogenesis) aims to elucidate the molecular mechanisms and role of MAX/MGA/MYC genetic perturbations in driving GIST pathogenesis and to develop novel biomarkers and predictive models to improve patient risk assessment and selection for adjuvant therapy. RP2 (Targeting Hippo Dependence) seeks to characterize the role of the Hippo pathway and the eIF4FA complex in genetically complex sarcomas, test the efficacy and toxicity of a new eIF4A inhibitor, TDI-7663, and develop biomarkers of innate and acquired resistance to eIF4A inhibition. RP3 (Synovial Sarcoma Vulnerabilities) seeks to identify novel epigenetic vulnerabilities and immuno-oncologic strategies in synovial sarcoma and potential synergies between them by discovering H3K36 methylation-related dependencies on specific epigenetic regulators, preclinical development of T cells genetically engineered to express a T cell receptor against the SS18::SSX public neoantigen, and a conceptually innovative clinical trial of a multivalent mRNA vaccine encoding the SS18::SSX(1/2) junction sequence and the major cancer-testis antigens in synovial sarcoma.