Background:The survival rate of patients with Ewing sarcoma (EWS) has seen very little improvement over the past several decades and remains dismal for those with recurrent or metastatic disease. HDAC2, ALK, JAK1, and CDK4 were identified as potential targets using RNA sequencing performed on EWS patient tumors with the bioinformatic analysis of gene expression.Methods/Results:The pan-HDAC inhibitor Panobinostat was cytotoxic to all the Ewing sarcoma cell lines tested. Mechanistically, Panobinostat decreases the expression of proteins involved in the cell cycle, including Cyclin D1 and phospho-Rb, and DNA damage repair, including CHK1. Further, Panobinostat induces a G1 cell cycle arrest. The combination of Panobinostat with Doxorubicin or Etoposide, both of which are used as standard of care in upfront treatment, leads to a synergistic effect in EWS cells. The combination of Panobinostat and Doxorubicin induces an accumulation of DNA damage, a decrease in the expression of DNA damage repair proteins CHK1 and CHK2, and an increase in caspase 3 cleavage. The addition of Panobinostat to standard-of-care chemotherapy combinations significantly reduces cell viability compared to that of chemotherapy alone.Conclusions:Overall, our data indicate that HDAC2 is overexpressed in many EWS tumor samples and HDAC inhibition is effective in targeting EWS cells, alone and in combination with standard-of-care chemotherapy agents. This work suggests that the addition of an HDAC inhibitor to upfront treatment may improve response.
背景：过去几十年间，尤文肉瘤（EWS）患者的生存率改善甚微，复发或转移性患者的预后尤其不佳。通过对尤文肉瘤患者肿瘤组织进行RNA测序及基因表达生物信息学分析，我们确定HDAC2、ALK、JAK1和CDK4为潜在治疗靶点。 方法/结果：泛HDAC抑制剂帕比司他对所有测试的尤文肉瘤细胞系均表现出细胞毒性作用。机制研究表明，帕比司他能够下调细胞周期相关蛋白（包括细胞周期蛋白D1和磷酸化Rb）及DNA损伤修复蛋白（如CHK1）的表达水平。此外，帕比司他可诱导细胞周期G1期阻滞。当帕比司他与标准一线治疗药物多柔比星或依托泊苷联用时，在尤文肉瘤细胞中产生协同效应。帕比司他与多柔比星联合用药可导致DNA损伤累积、DNA损伤修复蛋白CHK1和CHK2表达下调，并增强caspase 3剪切活化。与单纯化疗方案相比，在标准化疗方案中加入帕比司他能显著降低细胞活力。 结论：本研究数据显示HDAC2在众多尤文肉瘤肿瘤样本中过表达，而HDAC抑制剂单药或联合标准化疗药物均能有效靶向尤文肉瘤细胞。这项工作提示，在一线治疗方案中加入HDAC抑制剂可能提升治疗应答率。
肿瘤(癌症)患者之家