Pediatric and Young Adult Undifferentiated Round Cell Sarcomas beyond Ewing Sarcoma: Establishing in vitro Models and Discovery of Novel Therapeutic Targets of CIC::DUX4 Sarcoma
Undifferentiated round cell sarcomas (URCS) are a diverse group of tumors, identified by their round cell appearance under a microscope and a variety of chromosomal translocations. These tumors affect children and young adults and present with a broad range of clinical symptoms. Despite their genetic and clinical differences, patients are typically treated using similar approaches to Ewing sarcoma protocols. Ewing sarcoma, the most common and well-understood URCS, is characterized by the EWSR1::FLI1 fusion. Advances in chemoradiation have significantly improved outcomes for Ewing sarcoma, leading to 5-year survival rates exceeding 70%.
Much of the funding, ongoing research, and available treatment development have historically concentrated on Ewing sarcoma. However, with the widespread use of sequencing in clinical practice, it has become clear that sarcomas with CIC::DUX4 fusions are the second most common round cell sarcoma and are distinct from classic Ewing sarcoma. These sarcomas are highly aggressive, with a 5-year survival rate of only 40%, and are often resistant to Ewing sarcoma-based chemotherapy.
Our lab has been dedicated to investigating this disease, being among the first to identify CIC fusions and describe their poor clinical outcomes. Our work has led to the inclusion of CIC::DUX4 sarcomas as a standalone group of URCS in the WHO classification, separate from Ewing sarcoma. Despite this improved classification, the exact cause of this disease remains largely unknown. Furthermore, the absence of accurate in vivo (e.g., mouse) and in vitro (e.g., cell line) models that truly reflect the tumor’s genetic features has hampered both characterization and the development of new therapeutic approaches.
In this research, we aim to further understand the molecular basis of this understudied sarcoma by exploring potential genomic weaknesses and cellular-level differences throughout the disease’s progression. We will use single cell-resolution RNA sequencing (RNAseq), which is an ideal tool for investigating how CIC::DUX4 tumors evolve during different stages of treatment (before, after, and in resistant samples). This will allow us to better differentiate between sensitive and evolving resistant cell states. Additionally, we will develop reliable in vitro and in vivo models to study the role of CIC::DUX4 fusion in the development of cancer. Our comprehensive strategy combines genomic and CRISPR-Cas9 technologies, and will generate accurate models that mimic the characteristics of human disease.