Desmoplastic small round cell tumor (DSRCT) is an aggressive sarcoma type that kills more than sixty, mostly male children and young adults in the United States each year. Half of these patients receive care at MD Anderson, but no curative therapies exist, and most patients die within five years of diagnosis despite specialized multidisciplinary treatment. Though the causative EWS-WT1 fusion protein (FP) is expressed in every patient's tumor, it isn't targetable. As a work-around, one approach is to minimize the FP's adverse tumor-promoting downstream effects. Toward that end, our lab and others have recently discovered that the androgen receptor (AR), more commonly known for its role in p...

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Desmoplastic small round cell tumor (DSRCT) is an aggressive sarcoma type that kills more than sixty, mostly male children and young adults in the United States each year. Half of these patients receive care at MD Anderson, but no curative therapies exist, and most patients die within five years of diagnosis despite specialized multidisciplinary treatment. Though the causative EWS-WT1 fusion protein (FP) is expressed in every patient's tumor, it isn't targetable. As a work-around, one approach is to minimize the FP's adverse tumor-promoting downstream effects. Toward that end, our lab and others have recently discovered that the androgen receptor (AR), more commonly known for its role in prostate cancer, promotes DSRCT tumor growth and survival by altering how the genetic code is transcribed. Despite this exciting discovery, much remains to be determined. The precise epigenetic role of AR in DSRCT, for example, has just begun to be studied, and it remains a mystery how AR coordinates with other transcription factors (and the FP) to dysregulate cell fate. Additionally, since some DSRCTs harbor cells expressing neuroendocrine features that are often linked to drug resistance, it's unclear how drugs of proven value in prostate cancer will find utility for DSRCT. The current research addresses these seminal questions with three specific aims. Aim 1 uses advanced technologies to assess the individual cells that make up the entire tumor. This single-cell-based approach allows scientists to determine the cell composition of human DSRCT specimens, specifically the presence of AR+ epithelial cells (likely to be drug-sensitive) and AR- neuroendocrine cells (drug-resistant). Aim 2 delves deeply into the interactions between AR and the other proteins that affect AR function. Finally, Aim 3 performs lab experiments designed to estimate how the drugs more commonly used for prostate might optimally be used as novel treatments for kids diagnosed with DSRCT.

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