An Epigenetic Strategy for Restoring Carboplatin Sensitivity in Ovarian Cancer

描述（由申请人提供）：卵巢癌的铂耐药与表观遗传变化的积累有关，导致肿瘤抑制基因和化学反应性相关基因的转录沉默。先前设计和进行的一项临床试验表明，甲基组靶向干预可以逆转铂耐药并诱导临床反应。在此基础上，我们建议利用mbdcap测序和生物信息学技术扩展卵巢癌表观基因组分析，并测试新型DNA甲基转移酶抑制剂（DNMTI） SGI-110的作用。待验证的假设是，卵巢癌的铂耐药仅反映在DNA甲基化变化中，并且可以通过DNMTI逆转。为了验证这一假设，将对一项正在进行的随机II期临床试验收集的肿瘤和血浆样本进行分析，该试验将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。约100例患者的临床标本将可用于分析。提出了三个目标。对于Aim 1，将通过对SGI-110前后获得的肿瘤活检使用MethylCap-seq来测量dnmti诱导的卵巢癌甲基组变化。本目的目的是研究SGI-110是否诱导影响化学反应性相关基因网络的全局甲基组变化。Aim 2的目的是确定复发性肿瘤和原发肿瘤中DNMT表达水平是否不同，以及入组时的表达水平或DNMTIs引起的变化是否与临床获益相关。Aim 3的目的是确定入组时特定基因的甲基化水平和DNMTIs引起的变化是否与临床获益相关。该项目将确定控制铂耐药性发展的关键DNA甲基化事件。拟议的研究是高度创新的，基于使用最先进的MBDCap-Seq和生物信息学应用于高临床相关性的问题。本试验中相关工作的成功完成将确定对甲基组靶向策略反应的预测标记。这项研究将把表观遗传干预带到卵巢癌治疗的前沿，影响这种致命癌症的治疗策略和结果。该研究的成功完成将推动表观基因组靶向治疗实体瘤领域的发展，并将为未来生物学指导的III期试验设计提供关键信息。

DESCRIPTION (provided by applicant): 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 wil 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.