Molecular Determinants of Decitabine Response

地西他滨反应的分子决定因素

• 批准号: 8595785
• 负责人: TIMOTHY J. LEY
• 金额: $ 33.05万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-03 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8595785
• 关键词: Acute Myelocytic Leukemia; Affect; Azacitidine; Base Sequence; Biological Markers; Blast Cell; Bone Marrow; Clinical; Clinical assessments; Consent; Custom; DNA Methylation; Data; Decitabine; Disease; Disease-Free Survival; Dose; Dysmyelopoietic Syndromes; Frequencies; Gene Frequency; Gene Mutation; Gene Silencing; Genes; Genie; Genome; Genomics; Genotype; Goals; In complete remission; Instruction; Malignant Neoplasms; Marrow; Mass Spectrum Analysis; Measurement; Measures; Messenger RNA; Metabolism; MicroRNAs; Molecular; Molecular Profiling; Mutate; Mutation; Nature; Oligonucleotides; Outcome; Outpatients; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Protocols documentation; Research; Resistance; Sampling; Schedule; Sequence Analysis; Serum; Somatic Mutation; Stem cell transplant; Time; Tumor Burden; base; clinical decision-making; digital; drug metabolism; exome; exome sequencing; leukemia; molecular marker; mutant; overexpression; programs; response

The long term goal of this project is to identify the patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who are the most likely to respond to decitabine therapy. Decitabine is a hypomethylating agent that has efficacy in both MDS and AML. It can be given as an outpatient, and it is well tolerated in most patients. However, response rates are modest; even with modern aggressive schedules, only 4 5 % of patients achieve a complete response. The molecular basis of decitabine sensitivity and/or resistance is not yet clear. Specific Aims: Aim1.Wewilldefinethemolecularsignatureofdecitabineresponders.Wewillprospectivelybank125 properly consented patients treated with the current state-of-the-art decitabine protocol. We will comprehensively define patient-specific molecular signatures through exome sequencing and expression profiling, using both mRNA and miRNA based arrays. We will correlate genotyping and expression results with clinical features, including responsiveness to decitabine therapy. These studies will correlate genomic signatures of DNMT3A, I D H I , IDH2, and TET2 with outcomes. In addition, comprehensive, unbiased analysis will determine whether specific molecular signatures are associated with decitabine responses. Aim 2. We will determine whether the rate of AML clearance and persistence of AML-associated subclones corresponds tddrug metabolism, molecular, and/or clinical features of AML in each case. We will assess the velocity of patient-specific mutation clearance on day 0, 10, and 28, and the persistence of AML-associated subclones despite blast clearance. W e will correlate this with steiady-state decitabine drug levels, the reduction of methylcytosine in the total marrow sample (a biomarker of effective dosing), and with clinical response rates and event-free survival. RELEVANCE (See instructions): Many patients do not respond to decitabine therapy for AML or MDS. The causes of sensitivity and resistance are unknown. In this study we will optimize a pipeline for comprehensive molecular characterization of patient-specific mutations, expression profiles, and pharmacologic outcomes. We will determine whether molecular signatures predict response or resistance to decitabine.

该项目的长期目标是识别急性髓系白血病 (AML) 患者并 骨髓增生异常综合征 (MDS) 最有可能对地西他滨治疗产生反应。地西他滨是一种 去甲基化剂对 MDS 和 AML 均有效。可以门诊给的，效果很好 大多数患者可以耐受。然而，回应率并不高；即使采用现代积极的日程安排， 只有 4 5 % 的患者达到完全缓解。地西他滨敏感性的分子基础和/或 阻力尚不清楚。 具体目标： 目标1.我们将定义地西他滨反应者的分子特征。我们将前瞻性地储存125 经适当同意的患者接受当前最先进的地西他滨方案治疗。我们将 通过外显子组测序和表达全面定义患者特异性分子特征 使用基于 mRNA 和 miRNA 的阵列进行分析。我们将关联基因分型和表达结果 具有临床特征，包括对地西他滨治疗的反应。这些研究将基因组关联起来 DNMT3A、IDH1、IDH2 和 TET2 的签名及结果。此外，全面、公正 分析将确定特定的分子特征是否与地西他滨反应相关。 目标 2. 我们将确定 AML 清除率和 AML 相关亚克隆的持续性是否 对应每种情况下 AML 的药物代谢、分子和/或临床特征。我们将评估 第 0、10 和 28 天患者特异性突变清除的速度，以及 AML 相关突变的持续性 尽管爆炸清除了亚克隆。我们将把它与稳定状态的地西他滨药物水平联系起来， 总骨髓样本中甲基胞嘧啶的减少（有效剂量的生物标志物），并且与临床 有效率和无事件生存率。 相关性（参见说明）： 许多患者对地西他滨治疗 AML 或 MDS 没有反应。敏感的原因及 电阻未知。在这项研究中，我们将优化综合分子的管道 患者特异性突变、表达谱和药理学结果的表征。我们将 确定分子特征是否预测对地西他滨的反应或耐药性。