ABSTRACT – OVERALL Neurofibromatosis type 1 (NF1) is the most common inherited cancer predisposition syndrome of a group of developmental disorders that are collectively termed “Rasopathies”. Germline NF1 mutations cause neurofibromatosis type 1 (NF1), a multi-system developmental disorder that is also the most common inherited cancer predisposition syndrome. NF1 is of exceptional importance in cancer biology because it encodes a GTPase activating protein (GAP) called neurofibromin that binds to active Ras-GTP and terminates signaling by accelerating guanine nucleotide hydrolysis. Thus, NF1 inactivation and somatic cancer-associated RAS mutations result in constitutively elevated Ras-GTP levels and aberrant activation of Ras-regulated kinase effector pathways in susceptible cell lineages. A markedly increased incidence of developing specific benign and malignant tumors is a hallmark of NF1 that results in substantial morbidity and mortality that affect children, adolescents, and young adults (AYAs) in a range of tissues. Investigating NF1-associated tumors represents a unique opportunity to interrogate therapeutic responses and mechanisms of intrinsic and acquired drug resistance in cancers that are initiated by a mutation that directly enhances Ras output. Given the central importance of aberrant Ras/GAP function in human cancer, and the emerging role of somatic NF1 mutations in common sporadic malignancies, achieving the goals of this SPORE will broadly advance translational cancer research and treatment. The overall goal of this Developmental and Hyperactive Ras Tumor (DHART) SPORE is to implement effective targeted therapies for neoplasms and cancers characterized by mutations in the NF1 tumor suppressor gene (TSG) by conducting integrated, mechanistically based translational research. The DHART SPORE deploys novel organizing principles and approaches to address the key challenge of how to accelerate new therapies for uncommon (“orphan”) benign and malignant tumors across an organ spectrum with a common driver mutation. The DHART SPORE is comprised of a highly integrated group of translational scientists that are addressing central issues for implementing mechanism-based treatments for rare tumors driven by hyperactive Ras signaling in the pediatric, adolescent, and young adult (AYA) population. Across all three projects, state-of-the-art core facilities will inform the patient-oriented therapeutic and prevention aspects by delineating mutations that contribute to cancer pathogenesis, and by uncovering new biomarkers of drug response and resistance that will inform the development of “next generation” treatments. Achieving the objectives of the proposed Projects 1-3 will not only improve the outcomes of NF1 and non-NF1 patients with specific cancers but has the potential to inform new therapeutic approaches for the substantial proportion of human cancers characterized by somatic NF1 and RAS mutations that have implications for enhancing the ...