ABSTRACT
Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5α-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the C-terminal partner of the pathognomonic fusion protein) and FOXF1. Additionally, AR occupied enhancer sites that regulate the Wnt pathway, neural differentiation, and embryonic organ development, implicating AR in dysfunctional cell lineage commitment. Our findings have immediate clinical implications given the widespread availability of FDA-approved androgen-targeted agents used for prostate cancer.
ONE SENTENCE SUMMARY We demonstrate that DSRCT, an aggressive pediatric cancer, is an AR-driven malignancy capable of responding to androgen deprivation therapy.
Competing Interest Statement
Dr. MacLeod is an employee and shareholder of Ionis Pharmaceuticals.
Footnotes
↵* Co-first authors
Financial Disclosures: Dr. MacLeod is an employee and shareholder of Ionis Pharmaceuticals.
Research Support: The University of Texas MD Anderson Cancer Center is supported by the National Institutes of Health through Cancer Center Support Grant CA016672. JAL and AHJ are funded through the generous philanthropy of the Cory Monzingo Foundation.
