An Epigenetic Strategy for Restoring Carboplatin Sensitivity in Ovarian Cancer

描述（由申请人提供）：卵巢癌中的铂耐药性与表观遗传变化的积累相关，导致肿瘤抑制基因和化疗反应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，甲基化组靶向干预措施可逆转铂类耐药并诱导临床反应。在此工作的基础上，我们建议通过使用 MBDCap 测序和生物信息学来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)）的效果。待检验的假设是，卵巢癌中的铂类耐药性独特地反映在 DNA 甲基化变化上，并且可以通过 DNMTI 逆转。为了解决这一假设，将对从一项正在进行的随机 II 期临床试验中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 批准的铂耐药卵巢癌策略进行比较。来自约 100 名患者的临床标本将可供分析。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 MmethylCap-seq 来测量 DNMTI 诱导的卵巢癌甲基化组的变化。该目的的目的是研究 SGI-110 是否会诱导全局甲基化组变化，从而影响与化疗反应相关的基因网络。目标 2 的目的是确定 DNMT 表达水平在复发性肿瘤与原发性肿瘤中是否存在差异，以及入组时的表达水平或 DNMTIs 诱导的变化是否与临床获益相关。目标 3 的目标是确定入组时的特定基因甲基化水平以及 DNMTIs 诱导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。拟议的研究基于使用最先进的 MBDCap-Seq 和应用于高度临床相关问题的生物信息学，具有高度创新性。成功完成本试验中整合的相关工作将确定对甲基化组靶向策略反应的预测标记。这项研究将把表观遗传学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，并将为未来生物导向的 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.