Bexelius Tomas S, Wasti Ajla, Chisholm Julia C
Children and Young People's Unit, Royal Marsden Hospital NHS Foundation Trust, Sutton, United Kingdom.
Department of Women and Children Health at Karolinska Institutet, Stockholm, Sweden.
Front Oncol. 2020 Apr 21;10:518. doi: 10.3389/fonc.2020.00518. eCollection 2020.
Desmoplastic small round cell tumor (DSRCT) is a devastating disease which most commonly affects adolescents, with a male predominance. Despite the best multimodality treatment efforts, most patients will ultimately not survive more than 3-5 years after diagnosis. Some research trials in soft-tissue sarcoma and Ewing sarcoma include DSRCT patients but few studies have been tailored to the specific clinical needs and underlying cytogenetic abnormalities characterizing this disease such as the typical EWSR1-WT1 gene fusion. Downstream activation of EWSR1-WT1 gene fusion includes signaling pathways of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and insulin growth factor (IGF)-1. Other biological pathways that are activated and expressed in DSRCT cells include endothelial growth factor receptor (EGFR), androgen receptor pathway, c-KIT, MET, and transforming growth factor (TGF) beta. Investigation of somatic mutations, copy number alterations (CNA), and chromosomes in DSRCT samples suggests that deregulation of mesenchymal-epithelial reverse transition (MErT)/epithelial-mesenchymal transition (EMT) and DNA damage repair (DDR) may be important in DSRCT. This mini review looks at known druggable targets in DSRCT and existing clinical evidence for targeted treatments, particularly multityrosine kinase inhibitors such as pazopanib, imatinib, and sorafenib alone or in combination with other agents such as mTOR (mammalian target of rapamycin) inhibitors. The aim is to increase shared knowledge about current available treatments and identify gaps in research to further efforts toward clinical development of targeted agents.
促结缔组织增生性小圆细胞肿瘤（DSRCT）是一种严重的疾病，最常影响青少年，男性居多。尽管采取了最佳的多模式治疗措施，但大多数患者在确诊后最终存活时间不超过3至5年。一些软组织肉瘤和尤因肉瘤的研究试验纳入了DSRCT患者，但针对该疾病特定临床需求和潜在细胞遗传学异常（如典型的EWSR1-WT1基因融合）的研究很少。EWSR1-WT1基因融合的下游激活包括血小板衍生生长因子（PDGF）、血管内皮生长因子（VEGF）和胰岛素生长因子（IGF）-1的信号通路。在DSRCT细胞中激活并表达的其他生物学途径包括内皮生长因子受体（EGFR）、雄激素受体途径、c-KIT、MET和转化生长因子（TGF）β。对DSRCT样本中的体细胞突变、拷贝数改变（CNA）和染色体的研究表明，间充质-上皮逆转转变（MErT）/上皮-间充质转变（EMT）和DNA损伤修复（DDR）的失调在DSRCT中可能很重要。这篇综述探讨了DSRCT中已知的可成药靶点以及现有靶向治疗的临床证据，特别是多酪氨酸激酶抑制剂，如帕唑帕尼、伊马替尼和索拉非尼单独使用或与其他药物（如mTOR（雷帕霉素哺乳动物靶点）抑制剂）联合使用。目的是增加对当前可用治疗方法的共同了解，并确定研究中的差距，以进一步推动靶向药物的临床开发。
