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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 , 2022. "The androgen receptor is a therapeutic target in desmoplastic small round cell sarcoma," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30710-z
    DOI: 10.1038/s41467-022-30710-z
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    References listed on IDEAS

    as
    1. Jialiang Huang & Kailong Li & Wenqing Cai & Xin Liu & Yuannyu Zhang & Stuart H. Orkin & Jian Xu & Guo-Cheng Yuan, 2018. "Dissecting super-enhancer hierarchy based on chromatin interactions," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
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