Development of a Clinically Relevant Genetically Engineered Mouse Model for Human High-Risk Rhabdomyosarcoma

PROJECT SUMMARY The burgeoning field of cancer genomics has underscored the importance of genetically engineered mouse models (GEMMs) in elucidating the complexities of human cancer. These models offer invaluable insights into cancer drivers, cellular origins, heterogeneity, and therapeutic responses, bridging preclinical research and clinical predictions. Rhabdomyosarcoma (RMS), the most prevalent soft tissue sarcoma in children, presents a pressing clinical challenge with dismal prognosis rates, particularly in high-risk cases. Notably, aberrant activation of the NOTCH1 pathway is implicated in 60% of human RMS cases, correlating with poorer survival outcomes. Our overarching objective is to identify therapeutically relevant genetic factors and pathways that impede RMS progression and to develop targeted therapies for sarcoma cancer. Central to this proposal is exploring NOTCH1 pathway activation as both a driver and a therapeutic target in curbing RMS growth. Leveraging our expertise in GEMM development, our study aims to create the first mouse models that faithfully replicate key features of human RMS while also serving as platforms to evaluate Notch inhibition as a potential cancer therapy. In pursuit of this goal, aim one focuses on developing and characterizing RMS mouse models, including assessing drug effects on molecularly targeted agents that specifically modulate Notch activation, with a particular emphasis on exploring synergistic effects of dual pathway inhibition. Aim two seeks to model Notch inhibition as a targeted therapeutic approach in GEMMs. By integrating advanced molecular analyses with robust in vivo models, our comprehensive approach holds promise for revolutionizing the clinical management of Notch- driven RMS and other cancers with similar molecular profiles. Through this research, we seek to improve patient outcomes, advance public health, and pave the way for transformative advancements in cancer therapeutics.