Rhabdomyosarcoma: Current Therapy, Challenges, and Future Approaches to Treatment Strategies

Simple Summary Rhabdomyosarcoma (RMS) is a rare pediatric sarcoma affecting skeletal muscle in children and young adults. It is responsible for 3% of all childhood malignant tumors and is the third most prevalent pediatric extracranial solid tumor. Despite advances in diagnostic and treatment methods and clinical trials to improve pediatric RMS survival rates, children with high-risk RMS and recurrent disease have 5-year survival rates of less than 30% and 17%, respectively. The cure rate remains low and the current RMS therapies continue to pose potential life-threatening toxicities, which can lead to lifelong morbidity. The treatment strategies for RMS include multi-agent chemotherapies after surgical resection with or without radiotherapy. Here, we focus on chemotherapy strategies and discuss the impact of apoptosis, autophagy, and the UPR that are involved in the chemotherapy response. Then, to screen future therapeutic approaches and promote muscle regeneration, we discuss in vivo mouse and zebrafish models and in vitro three-dimensional bioengineering models.Abstract Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy. In this comprehensive review, we first provide a detailed clinical understanding of rhabdomyosarcoma including its classification and subtypes, diagnosis, and treatment strategies. Later, we focus on chemotherapy strategies for this childhood sarcoma and discuss the impact of three mechanisms that are involved in the chemotherapy response including apoptosis, macro-autophagy, and the unfolded protein response. Finally, we discuss in vivo mouse and zebrafish models and in vitro three-dimensional bioengineering models of rhabdomyosarcoma to screen future therapeutic approaches and promote muscle regeneration.