Desmoplastic small round cell tumor (DSRCT) is an aggressive cancer that primarily affects male pediatric and adolescent patients. The disease is caused by a specific genetic alteration that fuses two genes (Ewing sarcoma RNA-binding protein 1 (EWSR1) and Wilms’ tumor antigen 1 (WT1)) to create a potent cancer-causing gene, or “oncogene”, that drives growth of DSRCT. There are very few therapeutic options for this disease and overall survival is 15% at 5 years. One of the main reasons for this poor patient outcome is a lack of understanding of DSRCT biology, a likely consequence of a lack of disease models. The overall goal of our research is to develop a deeper understanding of DSRCT biology. This research is important because we hope to reveal biological secrets about how the EWSR1-WT1 oncogene hijacks cellular machinery to promote uncontrolled growth. These findings can be exploited to identify new therapeutic options to improve the prognosis of children and young adults battling this devastating cancer.

DSRCT is a very rare disease, which limits the opportunities to develop patient-derived tools such as cell lines and mouse models that would allow us to better understand its unique biology. Therefore, obtaining preclinical data with enough patient-derived models to justify starting clinical trials remains a major obstacle. Our work addresses this problem with the successful generation and characterization of novel patient-derived models. Specifically, our team developed and characterized six new DSRCT cell lines (only one existed previously) and twenty mouse models derived from human tumor samples. To further expand our research tools with a complementary approach, we engineered the EWSR1-WT1 oncogene in a normal cell line, using CRISPR/Cas9-mediated genome-engineering. Using our new models, we validated a signaling protein, epidermal growth factor receptor (EGFR), as a significant contributor to DSRCT growth. Furthermore, we demonstrated that targeting EGFR with drugs that are currently approved by the U.S. Food and Drug Administration (FDA) for other cancers can reduce growth of multiple DSRCT models. I am hopeful that these preclinical data will provide the justification for clinical trials to bring these findings to patients.

We will continue to build on and expand these strategies to better understand the fundamental biological pathways leading to DSRCT tumor formation. Future studies will employ our engineered and patient-derived models to dissect how each of the over 20,000 genes in the human genome play a role in DSRCT biology. These technologies empower researchers to ask big questions with a fraction of the resources required only a decade ago. Sharing these models and datasets with the scientific community will foster collaborations and accelerate progress to overcome this disease. As we refine our understanding of the complex interactions between genes and proteins in tumor cells, we can refine our therapeutic approach. Ultimately, the ability to generate new models of disease means that no cancer or disease is too rare to study. I am optimistic that we will achieve significant progress for patients suffering from cancer during my research career.

By Roger S. Smith

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