An Epigenetic Strategy for Restoring Carboplatin Sensitivity in Ovarian Cancer

项目摘要/摘要 卵巢癌中铂耐药与表观遗传改变的积累有关 肿瘤抑制基因和化疗反应相关基因的转录沉默。一项临床试验 之前设计和进行的研究表明，甲基组靶向干预逆转了铂 耐药并诱导临床反应。在这项工作的基础上，我们建议延长卵巢癌 应用MBDCap测序和生物信息学进行表观基因组分析及验证SGI-110的作用 新型DNA甲基转移酶抑制剂(DNMTI)。需要检验的假设是，铂金阻力在 卵巢癌独特地反映在DNA甲基化的变化上，并可以通过DNMTI逆转。至 从正在进行的随机二期临床试验中收集的肿瘤和血浆样本解决了这一假设 将SGI-110和卡铂与FDA批准的治疗铂耐药卵巢癌的策略进行比较 分析过了。将提供约100名患者的临床样本进行分析。提出了三个目标。为 目的1，用甲基帽序列技术检测DNMTI诱导的卵巢癌细胞甲基组的变化 SGI-110前后的肿瘤活检标本。此目的是调查SGI-110是否 诱导全球甲基组变化，影响与化学反应相关的基因网络。这个 目标2的目的是确定DNMT在复发肿瘤和原发肿瘤中的表达水平是否不同 登记时的表达水平或由DNMTI引起的变化是否与临床益处相关。为了达到目标 3，目标是确定特定基因在注册时的甲基化水平和由 DNMTIs与临床益处相关。该项目将确定关键DNA甲基化事件 铂电阻的发展。拟议的研究具有很高的创新性，基于对状态的使用 最先进的MBDCap-Seq和生物信息学应用于一个具有高度临床相关性的问题。成功完成 在这项试验中整合的相关工作将确定对甲基组靶向反应的预测标记 战略。这项研究将把表观遗传学干预带入卵巢癌治疗的前沿。 这种致命癌症的治疗策略和结果。这项研究的成功完成将使 推进表观基因组靶向治疗实体肿瘤领域，并将为生物学上的 指导第三阶段试验的未来设计。

Project Summary/Abstract Platinum resistance in ovarian cancer is associated with accumulation of epigenetic changes leading to transcriptional silencing of tumor suppressor and chemo-responsiveness-associated genes. A clinical trial designed and conducted previously demonstrated that methylome-targeted interventions reverse platinum resistance and induce clinical responses. Building upon this work, we propose to extend the ovarian cancer epigenome analysis by using MBDCap-sequencing and bioinformatics and to test the effects of SGI-110, a novel DNA methyl transferase inhibitor (DNMTI). The hypothesis to be tested is that platinum resistance in ovarian cancer is uniquely reflected in DNA methylation changes and can be reversed by DNMTI. To address this hypothesis, tumor and plasma samples collected from an ongoing randomized phase II clinical trial comparing SGI-110 and carboplatin to FDA-approved strategies for platinum-resistant ovarian cancer will be analyzed. Clinical specimens from ~100 patients will be available for analysis. Three aims are proposed. For Aim 1, DNMTI-induced changes in the ovarian cancer methylome will be measured by using MethylCap-seq on tumor biopsies obtained before and after SGI-110. The objective of this Aim is to investigate whether SGI-110 induces global methylome changes affecting networks of genes associated with chemo-responsiveness. The objective of Aim 2 is to determine whether DNMT expression levels differ in recurrent vs. primary tumors and whether expression levels at enrollment or changes induced by DNMTIs correlate with clinical benefit. For Aim 3, the objective is to determine whether specific genes methylation levels at enrollment and changes induced by DNMTIs correlate with clinical benefit. This project will identify critical DNA methylation events that govern the development of platinum resistance. The proposed studies are highly innovative based on the use of state-of- the-art MBDCap-Seq and bioinformatics applied to a question of high clinical relevance. Successful completion of the correlative work integrated in this trial will identify predictive markers of response to methylome-targeting strategies. This study will bring epigenetic interventions to the forefront of therapy for ovarian cancer impacting treatment strategies and outcomes for this deadly cancer. Successful completion of this study will move forward the field of epigenome-targeted therapy for solid tumors and will provide key information for biologically- directed future design of phase III trials.