Towards directed therapy for fusion-positive rhabdomyosarcoma

Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. The fusion-positive variant of rhabdomyosarcoma has the dubious distinction of being one of the most difficult to cure childhood cancers. Although the gene fusions PAX3::FOXO1 and PAX7::FOXO1 were discovered in the early 1990s, and since that time shown to be the molecular drivers of the disease, the best treatment to date still remains VAC (vincristine, actinomycin D, cyclophosphamide) combination therapy, first instituted as standard of care in the 1970s. Here we review the history, contemporary application, clinical evaluation, and future of fusion positive rhabdomyosarcoma systemic therapy. It is hoped that a better understanding of the underlying biology and the effective leverage of new strategies for targeting RNA, proteins, and the immune system will result in meaningful advances for treating this aggressive childhood cancer.