Desmoplastic Small Round Cell Tumor: A Review of Main Molecular Abnormalities and Emerging Therapy

Abstract

Desmoplastic small round cell tumor (DSRCT) is an extremely rare, aggressive sarcoma affecting adolescents and young adults with male predominance. Generally, it originates from the serosal surface of the abdominal cavity. The hallmark characteristic of DSRCT is the EWSR1-WT1 gene fusion. This translocation up-regulates the expression of PDGFRα, VEGF and other proteins related to tumor and vascular cell proliferation. Current management of DSRCT includes a combination of chemotherapy, radiation and aggressive cytoreductive surgery plus intra-peritoneal hyperthermic chemotherapy (HIPEC). Despite advances in multimodal therapy, outcomes remain poor since the majority of patients present disease recurrence and die within three years. The dismal survival makes DSRCT an orphan disease with an urgent need for new drugs. The treatment of advanced and recurrent disease with tyrosine kinase inhibitors, such as pazopanib, sunitinib, and mTOR inhibitors was evaluated by small trials. Recent studies using comprehensive molecular profiling of DSRCT identified potential therapeutic targets. In this review, we aim to describe the current studies conducted to better understand DSRCT biology and to explore the new therapeutic strategies under investigation in preclinical models and in early phase clinical trials.

Keywords: chemotherapy; desmoplastic small round cell tumor; prognosis; radiotherapy; rare disease; surgery; target therapy; treatment; tyrosine kinase receptor.

Figure 1

Therapeutic options for desmoplastic small round cell tumor (DSRCT). Based on multiple retrospectives and few prospective studies, the benefit was observed for therapies in green, low evidence of the benefit for therapies in blue. For relapsed or progressive disease, strategies in yellow had been used and in white are perspectives. HIPEC (hyperthermic intraperitoneal chemotherapy), RTKi (Receptor Tyrosine Kinase inhibition), ARi (Androgen Receptor inhibition), VEGFi (Vascular Endothelial Growth Factor inhibition), IO (immune check point inhibition), IGFi (Insulin Growth Factor inhibiotion), mTORi (mammalian Target of Rapamycin inhibition), ABMT (autologous bone marrow transplant).

Figure 2

Schematic representation of EWS–WT1 fusion protein mechanism of action in desmoplastic small round cell tumor. Increase in tyrosine-kinase receptor expression, modulation of DNA replication proteins, activation of DNA-Damage Repair (DRR) machinery resulting in proliferation, desmoplasia, neo-angiogenesis and drug resistance.