An Epigenetic Strategy for Restoring Carboplatin Sensitivity in Ovarian Cancer

恢复卵巢癌卡铂敏感性的表观遗传学策略

• 批准号: 8627405
• 负责人: Daniela E Matei
• 金额: $ 32.37万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-14 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627405
• 关键词: Address; Affect; Bioinformatics; Biological Markers; Biopsy; Cancer Model; Carboplatin; Clinical; Clinical Trials Design; Correlative Study; DNA; DNA Methylation; DNA mapping; Decitabine; Development; Disease; Drug resistance; Enrollment; Epigenetic Process; Event; FDA approved; Future; Genes; Genetic; Goals; Hematologic Neoplasms; Histone Deacetylation; Intervention; Liposomes; Malignant Neoplasms; Malignant neoplasm of ovary; Massive Parallel Sequencing; Measures; Methylation; Outcome; Paclitaxel; Patients; Pharmacologic Substance; Phase II Clinical Trials; Phase III Clinical Trials; Physicians; Plasma; Platinum; Pre-Clinical Model; Primary Neoplasm; Protocols documentation; Randomized; Recurrence; Regimen; Relapse; Research Design; Research Personnel; Resistance; Sampling; Solid Neoplasm; Specimen; Staging; Survival Rate; Testing; Therapeutic Clinical Trial; Therapeutic Intervention; Time; Topotecan; Transferase; Treatment outcome; Tumor Suppressor Proteins; Woman; Work; base; cancer initiation; cancer therapy; chemotherapy; clinically relevant; density; design; epigenome; epigenomics; gene discovery; histone modification; inhibitor/antagonist; innovation; methylome; novel; public health relevance; response; response marker; treatment strategy; trial comparing; tumor; tumor progression

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.

项目总结/摘要 卵巢癌中的铂耐药与表观遗传变化的积累相关， 肿瘤抑制和化学反应相关基因的转录沉默。临床试验 先前设计和进行的研究表明，甲基化靶向干预逆转了铂 耐药性并诱导临床反应。在这项工作的基础上，我们建议将卵巢癌 使用MBDCap-测序和生物信息学进行表观基因组分析，并测试SGI-110的作用 新的DNA甲基转移酶抑制剂（DNMTI）。待检验的假设是， 卵巢癌是唯一反映在DNA甲基化的变化，可以逆转DNMTI。到 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SGI-110和卡铂与FDA批准的铂类耐药卵巢癌治疗策略进行比较， 分析了约100例患者的临床标本可用于分析。提出了三个目标。为 目的1，将通过使用MethylCap-seq检测DNMTI诱导的卵巢癌甲基化组的变化。 在SGI-110之前和之后获得的肿瘤活组织检查。本目标的目的是调查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。的 目的2的目的是确定复发性肿瘤与原发性肿瘤中DNMT表达水平是否不同， 是否在登记时的表达水平或由DNMTIs诱导的变化与临床益处相关。为宗旨 3、目的是确定是否有特定基因在入组时甲基化水平的变化所诱导 DNMTI与临床获益相关。该项目将确定关键的DNA甲基化事件， 铂电阻的发展。拟议的研究是高度创新的基础上使用的国家- 最新的MBDCap-Seq和生物信息学应用于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确定对甲基化靶向反应的预测标志物 战略布局这项研究将把表观遗传干预带到卵巢癌治疗的最前沿， 治疗策略和结果。成功完成这项研究将推动 推进了实体瘤表观基因组靶向治疗领域，并将为生物学- 指导未来III期试验的设计。