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

Salah-Eddine Lamhamedi-Cherradi (), Mayinuer Maitituoheti, Brian A. Menegaz, Sandhya Krishnan, Amelia M. Vetter, Pamela Camacho, Chia-Chin Wu, Hannah C. Beird, Robert W. Porter, Davis R. Ingram, Vandhana Ramamoorthy, Sana Mohiuddin, David McCall, Danh D. Truong, Branko Cuglievan, P. Andrew Futreal, Alejandra Ruiz Velasco, Nazanin Esmaeili Anvar, Budi Utama, Mark Titus, Alexander J. Lazar, Wei-Lien Wang, Cristian Rodriguez-Aguayo, Ravin Ratan, J. Andrew Livingston, Kunal Rai (), A. Robert MacLeod, Najat C. Daw, Andrea Hayes-Jordan and Joseph A. Ludwig ()
Additional contact information
Salah-Eddine Lamhamedi-Cherradi: The University of Texas MD Anderson Cancer Center
Mayinuer Maitituoheti: The University of Texas MD Anderson Cancer Center
Brian A. Menegaz: Breast surgical Oncology, Baylor College of Medicine
Sandhya Krishnan: The University of Texas MD Anderson Cancer Center
Amelia M. Vetter: The University of Texas MD Anderson Cancer Center
Pamela Camacho: Texas Children’s Cancer & Hematology Centers
Chia-Chin Wu: The University of Texas MD Anderson Cancer Center
Hannah C. Beird: The University of Texas MD Anderson Cancer Center
Robert W. Porter: The University of Texas MD Anderson Cancer Center
Davis R. Ingram: The University of Texas MD Anderson Cancer Center
Vandhana Ramamoorthy: The University of Texas MD Anderson Cancer Center
Sana Mohiuddin: The University of Texas MD Anderson Cancer Center
David McCall: The University of Texas MD Anderson Cancer Center
Danh D. Truong: The University of Texas MD Anderson Cancer Center
Branko Cuglievan: The University of Texas MD Anderson Cancer Center
P. Andrew Futreal: The University of Texas MD Anderson Cancer Center
Alejandra Ruiz Velasco: The University of Texas MD Anderson Cancer Center
Nazanin Esmaeili Anvar: The University of Texas MD Anderson Cancer Center
Budi Utama: Rice University
Mark Titus: The University of Texas MD Anderson Cancer Center
Alexander J. Lazar: The University of Texas MD Anderson Cancer Center
Wei-Lien Wang: The University of Texas MD Anderson Cancer Center
Cristian Rodriguez-Aguayo: The University of Texas MD Anderson Cancer Center
Ravin Ratan: The University of Texas MD Anderson Cancer Center
J. Andrew Livingston: The University of Texas MD Anderson Cancer Center
Kunal Rai: The University of Texas MD Anderson Cancer Center
A. Robert MacLeod: Ionis Pharmaceuticals
Najat C. Daw: The University of Texas MD Anderson Cancer Center
Andrea Hayes-Jordan: Lineberger Comprehensive Cancer Center, UNC
Joseph A. Ludwig: The University of Texas MD Anderson Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-16

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

Date: 2022
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DOI: 10.1038/s41467-022-30710-z

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