Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Clin Cancer Res. 2013 Jul 15;19(14):4008-16. doi: 10.1158/1078-0432.CCR-13-0033. Epub 2013 May 29.
Agents that target the epigenome show activity in breast cancer models. In preclinical studies, the histone deacetylase inhibitor vorinostat induces cell-cycle arrest, apoptosis, and differentiation. We evaluated biomarker modulation in breast cancer tissues obtained from women with newly diagnosed invasive disease who received vorinostat and those who did not.
Tumor specimens were collected from 25 women who received up to 6 doses of oral vorinostat 300 mg twice daily and from 25 untreated controls in a nonrandomized study. Candidate gene expression was analyzed by reverse transcription PCR (RT-PCR) using the Oncotype DX 21-gene assay, and by immunohistochemistry for Ki-67 and cleaved caspase-3. Matched samples from treated women were analyzed for gene methylation by quantitative multiplex methylation-specific PCR (QM-MSP). Wilcoxon nonparametric tests were used to compare changes in quantitative gene expression levels pre- and post-vorinostat with changes in expression in untreated controls, and changes in gene methylation between pre- and post-vorinostat samples.
Vorinostat was well tolerated and there were no study-related delays in treatment. Compared with untreated controls, there were statistically significant decreases in the expression of proliferation-associated genes Ki-67 (P = 0.003), STK15 (P = 0.005), and Cyclin B1 (P = 0.03) following vorinostat, but not in other genes by the Oncotype DX assay, or in expression of Ki-67 or cleaved caspase-3 by immunohistochemistry. Changes in methylation were not observed.
Short-term vorinostat administration is associated with a significant decrease in expression of proliferation-associated genes in untreated breast cancers. This demonstration of biologic activity supports investigation of vorinostat in combination with other agents for the management of breast cancer.
靶向表观基因组的药物在乳腺癌模型中具有活性。在临床前研究中，组蛋白去乙酰化酶抑制剂伏立诺他诱导细胞周期停滞、细胞凋亡和分化。我们评估了新诊断为浸润性疾病的女性在接受伏立诺他和未接受伏立诺他治疗的患者的乳腺癌组织中的生物标志物变化。
在一项非随机研究中，从 25 名接受多达 6 剂口服伏立诺他 300mg，每日两次的女性和 25 名未接受治疗的对照组女性中收集肿瘤标本。采用逆转录聚合酶链反应（RT-PCR）检测候选基因表达，采用 Oncotype DX 21 基因检测、Ki-67 和 cleaved caspase-3 免疫组化检测。用定量多重甲基化特异性 PCR（QM-MSP）分析治疗女性的匹配样本的基因甲基化。采用 Wilcoxon 非参数检验比较伏立诺他治疗前后定量基因表达水平的变化与未接受治疗对照组的变化，以及伏立诺他治疗前后样本中基因甲基化的变化。
伏立诺他耐受性良好，治疗无相关延迟。与未接受治疗的对照组相比，伏立诺他治疗后增殖相关基因 Ki-67（P=0.003）、STK15（P=0.005）和 Cyclin B1（P=0.03）的表达显著降低，但 Oncotype DX 检测的其他基因或 Ki-67 或 cleaved caspase-3 的免疫组化表达未见变化。未观察到甲基化的变化。
短期伏立诺他给药与未接受治疗的乳腺癌中增殖相关基因的表达显著降低有关。这种生物活性的证明支持伏立诺他与其他药物联合用于乳腺癌的治疗。
