Fang Fang, Zuo Qingyao, Pilrose Jay, Wang Yinu, Shen Changyu, Li Meng, Wulfridge Phillip, Matei Daniela, Nephew Kenneth P
Medical Sciences, Indiana University School of Medicine, Bloomington, IN, USA.
Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA; VA Roudebush Hospital, Indianapolis, IN, USA; Department of Obstetrics and Gynecology; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Oncotarget. 2014 Jun 15;5(11):3579-89. doi: 10.18632/oncotarget.1961.
Combination therapy with decitabine, a DNMTi and carboplatin resensitized chemoresistant ovarian cancer (OC) to platinum inducing promising clinical activity. We investigated gene-expression profiles in tumor biopsies to identify decitabine-reactivated pathways associated with clinical response. Gene-expression profiling was performed using RNA from paired tumor biopsies before and 8 days after decitabine from 17 patients with platinum resistant OC. Bioinformatic analysis included unsupervised hierarchical-clustering, pathway and GSEA distinguishing profiles of "responders" (progression-free survival, PFS>6 months) and "non-responders" (PFS< 6 months). Functional validation of selected results was performed in OC cells/tumors. Pre-treatment tumors from responders expressed genes associated with enhanced glycosphingolipid biosynthesis, translational misregulation, decreased ABC transporter expression, TGF-β signaling, and numerous metabolic pathways. Analysis of post-treatment biopsies from responders revealed overexpression of genes associated with reduced Hedgehog pathway signaling, reduced DNA repair/replication, and cancer-associated metabolism. GO and GSEA analyses revealed upregulation of genes associated with glycosaminoglycan binding, cell-matrix adhesion, and cell-substrate adhesion. Computational findings were substantiated by experimental validation of expression of key genes involved in two critical pathways affected by decitabine (TGF-β and Hh). Gene-expression profiling identified specific pathways altered by decitabine and associated with platinum-resensitization and clinical benefit in OC. Our data could influence patient stratification for future studies using epigenetic therapies.
地西他滨（一种DNA甲基转移酶抑制剂）与卡铂联合治疗使化疗耐药的卵巢癌（OC）对铂重新敏感，展现出了有前景的临床活性。我们研究了肿瘤活检组织中的基因表达谱，以确定与临床反应相关的地西他滨重新激活的通路。对17例铂耐药OC患者在使用地西他滨前及用药8天后的配对肿瘤活检组织的RNA进行基因表达谱分析。生物信息学分析包括无监督层次聚类、通路分析以及基因集富集分析（GSEA），以区分“反应者”（无进展生存期，PFS>6个月）和“无反应者”（PFS<6个月）的特征。在OC细胞/肿瘤中对选定结果进行功能验证。反应者的治疗前肿瘤表达与鞘糖脂生物合成增强、翻译失调、ABC转运蛋白表达降低、TGF-β信号传导以及众多代谢途径相关的基因。对反应者治疗后活检组织的分析显示，与刺猬信号通路信号传导减弱、DNA修复/复制减少以及癌症相关代谢相关的基因过表达。基因本体（GO）和GSEA分析显示与糖胺聚糖结合、细胞-基质粘附和细胞-底物粘附相关的基因上调。通过对受地西他滨影响的两个关键通路（TGF-β和Hh）中涉及的关键基因表达进行实验验证，证实了计算结果。基因表达谱分析确定了地西他滨改变的特定通路，这些通路与OC中的铂重新致敏和临床获益相关。我们的数据可能会影响未来使用表观遗传疗法的研究中的患者分层。
