Truong Danh D, Cardenas-Zuniga Roberto, Ludwig Joseph A
Department of Sarcoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
MD Anderson Cancer Center, 4SCR2.1040 1901 East Road, Houston, TX, 77054, USA.
Curr Treat Options Oncol. 2025 Jun 19. doi: 10.1007/s11864-025-01334-4.
Desmoplastic small round cell tumor (DSRCT) is an aggressive soft-tissue sarcoma driven by the EWSR1::WT1 fusion protein resulting from a chromosomal translocation between the EWSR1 (Ewing sarcoma breakpoint region 1) gene on chromosome 22 and the WT1 (Wilms tumor 1) gene on chromosome 11. This disease typically occurs in post-pubertal adolescent and young adult males, which suggests it may be hormonally driven through the androgen receptor (AR) pathway. Over the years, various groups have established a relationship between AR and DSRCT. Profiling studies have noted a high expression of AR in DSRCT. Fine et al. showed that combined androgen blockade led to a clinical benefit in three (all male) of six patients with stable disease or at least a minor response lasting three months. The AR pathway is relevant not only in prostate cancer but has been discovered to be oncogenic in salivary gland cancers, melanoma, and breast cancer. Though numerous AR-directed therapies are available to treat prostate cancer, AR has not been extensively evaluated as a therapeutic target in DSRCT. Preclinical studies revealed that AR stimulation increased cell proliferation. Conversely, single-agent targeting of the pathway delayed tumor growth in xenograft models. Pharmacodynamic analysis showed that AR inhibition activates the PI3K/Akt/mTOR pathway, and recent epigenetic analysis of AR binding showed that it may interact with EWSR1::WT1 and the forkhead protein family of transcription factors that regulate development and cellular differentiation. A deeper understanding of the impact of AR on the epigenetic landscape and signaling pathway crosstalk of DSRCT promises to expand the therapeutic arsenal of agents available to combat this deadly disease.
促纤维组织增生性小圆细胞肿瘤（DSRCT）是一种侵袭性软组织肉瘤，由EWSR1::WT1融合蛋白驱动，该融合蛋白是由22号染色体上的EWSR1（尤文肉瘤断点区域1）基因与11号染色体上的WT1（威尔姆斯瘤1）基因之间的染色体易位产生的。这种疾病通常发生在青春期后及年轻成年男性中，这表明它可能是由雄激素受体（AR）途径的激素驱动的。多年来，多个研究团队已经证实了AR与DSRCT之间的关联。分析研究表明DSRCT中AR的高表达。法恩等人发现，联合雄激素阻断疗法使6例病情稳定或至少有持续3个月轻微反应的患者中的3例（均为男性）临床获益。AR途径不仅与前列腺癌相关，还被发现与唾液腺癌、黑色素瘤和乳腺癌的致癌作用有关。尽管有许多针对AR的疗法可用于治疗前列腺癌，但AR尚未作为DSRCT的治疗靶点进行广泛评估。临床前研究显示，AR刺激会增加细胞增殖。相反，在异种移植模型中，单药靶向该途径可延缓肿瘤生长。药效学分析表明，AR抑制会激活PI3K/Akt/mTOR途径，最近对AR结合的表观遗传学分析表明，它可能与EWSR1::WT1以及调节发育和细胞分化的叉头蛋白家族转录因子相互作用。深入了解AR对DSRCT表观遗传格局和信号通路串扰的影响，有望扩大对抗这种致命疾病的可用治疗药物库。
