An Epigenetic Strategy for Restoring Carboplatin Sensitivity in Ovarian Cancer

描述(申请人提供)：卵巢癌的铂耐药与表观遗传改变的积累有关，导致肿瘤抑制基因和化疗反应相关基因的转录沉默。之前设计和进行的一项临床试验表明，甲基组靶向干预逆转了铂耐药并诱导了临床反应。在这项工作的基础上，我们建议利用MBDCap测序和生物信息学来扩展卵巢癌表观基因组分析，并测试新型DNA甲基转移酶抑制剂(DNMTI)SGI-110的效果。需要检验的假设是，卵巢癌对铂的耐药性唯一地反映在DNA甲基化的变化上，并可以被DNMTI逆转。为了解决这一假设，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将被分析，该试验比较了SGI-110和卡铂与FDA批准的铂耐药卵巢癌治疗策略。将提供约100名患者的临床样本进行分析。提出了三个目标。对于目标1，DNMTI诱导的卵巢癌甲基组的变化将通过使用在SGI-110之前和之后获得的肿瘤活检组织的甲基化序列来测量。其目的是调查SGI-110是否诱导影响与化疗反应相关的基因网络的全球甲基组变化。目标2的目的是确定DNMT的表达水平在复发性肿瘤和原发肿瘤中是否不同，以及DNMT在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。对于目标3，目标是确定登记时的特定基因甲基化水平和DNMTI引起的变化是否与临床益处相关。该项目将确定管理铂耐药性发展的关键DNA甲基化事件。建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一个具有高度临床相关性的问题。成功完成这项试验中整合的相关工作将确定对甲基组靶向策略的反应的预测性标记。这项研究将把表观遗传学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。这项研究的成功完成将推动表观基因组靶向治疗实体肿瘤的领域向前发展，并将为未来以生物为导向的第三阶段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.