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The Androgen Receptor: A Therapeutic Target In Desmoplastic Small Round Cell Sarcoma

ABSTRACT: The Androgen Receptor: A Therapeutic Target In Desmoplastic Small Round Cell Sarcoma

PROVIDER: PRJNA738891 | ENA |

REPOSITORIES: ENA

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The Androgen Receptor: A Therapeutic Target In Desmoplastic Small Round Cell Sarcoma

Project description: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 AR-directed antisense oligonucleotides (AR-ASO) block 5-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduced xenograft tumor burden. RPPA analysis was performed to elucidate how AR signaling regulates cellular programs. To gain a preliminary understanding of the short-term pharmacodynamic effects of AR suppression, a group of JN-DSRCT xenografts was collected 10 days into their AR-ASO treatment for analysis by RPPA to assess early compensatory pharmacodynamic changes. Its blockade has long been of interest in managing prostate cancer, where a compensatory increase in AKT signaling has been reported following AR inhibition. Therefore, these results collectively validate another proof of concept of AR-based antisense activity in DSRCT and suggest a clinical path forward since the AR-ASO (AZD5312) was safe, and often effective, in PC patients (NCT03300505). Our findings have immediate clinical implications given the widespread availability of FDA-approved androgen-targeted agents used for prostate cancer.

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Exome and transcriptome sequencing of Desmoplastic Small Round Cell Sarcoma

Project description:To conduct exome and transcriptome profiling to identify secondary recurrent mutations, multi-site phylogenetic analyse and immune characterization of Desmoplastic Small Round Cell Sarcoma.

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The androgen receptor is a therapeutic target in desmoplastic small round cell sarcoma.

Project description: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 direct clinical implications given the widespread availability of FDA-approved androgen-targeted agents used for prostate cancer.

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Project description:Desmoplastic Small Round Cell Tumor (DSRCT) is a rare, aggressive sarcoma driven by the EWSR1-WT1 chimeric transcription factor. Despite this unique oncogenic driver, DSRCT displays a polyphenotypic differentiation of unknown causality. Using single-cell multi-omics on samples from patients, we find that DSRCT tumor cells cluster into consistant subpopulations with partially overlapping lineage- and metabolism-related transcriptional programs.

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