An Epigenetic Strategy for Restoring Carboplatin Sensitivity in Ovarian Cancer

描述（由申请方提供）：卵巢癌中的铂类耐药与表观遗传学变化的积累相关，表观遗传学变化导致肿瘤抑制基因和化学反应相关基因的转录沉默。先前设计和进行的临床试验表明，甲基化靶向干预可逆转铂类耐药性并诱导临床反应。在这项工作的基础上，我们建议通过使用MBDCap测序和生物信息学扩展卵巢癌表观基因组分析，并测试SGI-110，一种新型DNA甲基转移酶抑制剂（DNMTI）的影响。有待检验的假设是，卵巢癌中的铂类耐药独特地反映在DNA甲基化变化中，并且可以被DNMTI逆转。为了解决这一假设，将分析从正在进行的随机II期临床试验中收集的肿瘤和血浆样本，该试验将SGI-110和卡铂与FDA批准的铂耐药卵巢癌策略进行比较。约100例患者的临床标本可用于分析。提出了三个目标。对于目标1，将通过对SGI-110之前和之后获得的肿瘤活检使用MethylCap-seq来测量DNMTI诱导的卵巢癌甲基化组的变化。本研究的目的是研究SGI-110是否诱导影响与化学反应性相关的基因网络的整体甲基化组变化。目的2的目的是确定复发性肿瘤与原发性肿瘤中的DNMT表达水平是否不同，以及入组时的表达水平或DNMTI诱导的变化是否与临床获益相关。对于目标3，目的是确定入组时的特定基因甲基化水平和DNMTIs诱导的变化是否与临床获益相关。该项目将确定决定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础上使用最先进的MBDCap-Seq和生物信息学应用于一个高度临床相关性的问题。成功完成本试验中整合的相关工作将鉴定对甲基化靶向策略的响应的预测标志物。这项研究将把表观遗传干预带到卵巢癌治疗的最前沿，影响这种致命癌症的治疗策略和结果。这项研究的成功完成将推动实体瘤表观基因组靶向治疗领域的发展，并将为未来III期试验的生物学导向设计提供关键信息。

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.