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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要卵巢癌的铂耐药性与表观遗传变化的积累有关，导致肿瘤抑制基因和化疗反应相关基因的转录沉默。临床试验先前设计和进行的研究表明，甲基组靶向干预措施可逆转铂耐药性并诱导临床反应。在此工作的基础上，我们建议扩大卵巢癌的治疗范围使用 MBDCap 测序和生物信息学进行表观基因组分析，并测试 SGI-110（一种新型 DNA 甲基转移酶抑制剂 (DNMTI)。要测试的假设是铂电阻卵巢癌独特地反映在DNA甲基化变化上，并且可以通过DNMTI逆转。到为了解决这一假设，从正在进行的随机 II 期临床试验中收集了肿瘤和血浆样本将 SGI-110 和卡铂与 FDA 批准的铂耐药卵巢癌策略进行比较分析了。来自约 100 名患者的临床标本将可供分析。提出了三个目标。为了目标 1，将使用 MmethylCap-seq 测量 DNMTI 诱导的卵巢癌甲基化组变化 SGI-110 之前和之后获得的肿瘤活检。该目标的目的是调查 SGI-110 是否诱导全局甲基化组变化，影响与化疗反应相关的基因网络。这目标 2 的目标是确定 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。为了目标 3，目的是确定入组时特定基因的甲基化水平是否会引起变化 DNMTIs 与临床获益相关。该项目将确定控制DNA甲基化的关键事件铂电阻的开发。拟议的研究基于使用现状，具有高度创新性最先进的 MBDCap-Seq 和生物信息学应用于具有高度临床相关性的问题。顺利完成该试验中整合的相关工作将确定甲基化组靶向反应的预测标记策略。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。顺利完成这项研究将推动推进实体瘤表观基因组靶向治疗领域的发展，并将为生物学研究提供关键信息指导未来 III 期试验的设计。