Project 1 - Molecular Determinants of Decitabine Responses.

项目 1 - 地西他滨反应的分子决定因素。

• 批准号: 10194399
• 负责人: TIMOTHY J. LEY
• 金额: $ 27.61万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194399
• 关键词: Acute Myelocytic Leukemia; Allogenic; Apoptosis; Bone Marrow; Clinical; Consolidation Therapy; Cytarabine; Cytotoxic Chemotherapy; DNA; DNA Damage; DNA Methylation; Data; Decitabine; Diagnosis; Disease remission; Event; Fred Hutchinson Cancer Research Center; Gene Expression Profile; Genes; Genome; Genomics; Goals; Guidelines; Homologous Transplantation; Iowa; Length of Stay; Methylation; Molecular; Morphology; Multivariate Analysis; Mutate; Mutation; Neoadjuvant Therapy; Outcome; Outpatients; Pathogenesis; Pathway interactions; Patients; Pattern; Point Mutation; Prognostic Marker; Recurrence; Refractory; Regimen; Relapse; Reporting; Resistance; Risk; Salvage Therapy; Sampling; Specialized Program of Research Excellence; Structure; Survival Rate; TP53 gene; TP53-mutant acute myeloid leukemia; Therapeutic; Time; Transplantation; Universities; Untranslated RNA; Variant; Washington; base; bisulfite sequencing; conditioning; design; epigenomics; exome; genome sequencing; hematopoietic cell transplantation; high risk; high risk population; improved; improved outcome; leukemia; leukemia relapse; mutant; patient population; primary endpoint; relapse risk; response; secondary endpoint; transcriptome sequencing; whole genome

Project Summary The long-term goal of this project is to identify the patients with acute myeloid leukemia (AML) who are the most likely to respond to decitabine therapy, and to determine the molecular mechanisms of decitabine responses. We recently reported that TP53 mutated AML and MDS patients, which have a high risk of relapse, and very poor outcomes, respond consistently to decitabine, a hypomethylating agent that can be given as an outpatient, and which is well tolerated in most patients. However, most responding patients did not have TP53 mutations, suggesting that other pathways can also influence decitabine sensitivity. The molecular mechanisms associated with decitabine responses and subsequent relapse are currently unclear. To refine and extend these findings, we propose the following specific aims: Aim 1. We will determine the efficacy of decitabine salvage therapy in AML patients with TP53 mutations. Patients with relapsed/refractory AML and with TP53 mutations represent an ultra-high-risk population with extremely poor outcomes, representing an unmet therapeutic need. We will therefore treat 60 relapsed/refractory AML patients known to have TP53 mutations with decitabine on days 1-10 of 28-day cycles at 3 centers (Washington University, Fred Hutchinson Cancer Research Center, and the University of Iowa). Responding patients will undergo allogeneic transplantation for consolidation therapy, if possible. We will determine the overall survival at 1 year, as well as response rates, time to transplant, time to leukemia relapse, and the average number of hospital days during cycles 1 and 2. Aim 2. We will define the genomic and epigenomic signatures associated with decitabine responses. We will use enhanced whole genome sequencing to determine whether TP53 wild-type patients have recurrent, non-genic mutations, and whether recurrent mutations are acquired at relapse, regardless of TP53 status. We will integrate whole genome bisulfite sequencing with RNA-Seq to determine whether decitabine causes specific and canonical patterns of DNA hypomethylation, whether these changes result in consistent transcriptional signatures, and whether any of these patterns correlate with clinical outcomes.

项目摘要 该项目的长期目标是确定患有急性髓性白血病（AML）的患者 最有可能对去班滨治疗做出反应，并确定 解滨反应。我们最近报道了TP53突变的AML和MDS患者，它们的患者高 复发的风险和非常差的结果，对Decitabine持续反应，Decitabine是一种可以 作为门诊病人，并且在大多数患者中都可以耐受。但是，大多数反应的患者确实 没有TP53突变，表明其他途径也会影响去替替滨的敏感性。这 目前尚不清楚与去替替滨反应和随后复发相关的分子机制。 为了完善和扩展这些发现，我们提出以下具体目的： AIM 1。我们将确定Decitabine打捞疗法在TP53患者中的疗效 突变。复发/难治性AML和具有TP53突变的患者代表超高风险 预后极差的人群，代表未满足的治疗需求。因此，我们将对待60 复发/难治性的AML患者已知在28天周期的1-10天已知具有TP53突变 在3个中心（华盛顿大学，弗雷德·哈钦森癌症研究中心和爱荷华大学）。 反应的患者将接受同种异体移植以进行巩固疗法。我们将 确定1年的总生存期以及响应率，移植时间，白血病复发的时间， 以及周期1和2期间的平均医院天数。 AIM 2。我们将定义与Decitabine反应相关的基因组和表观基因组信号。 我们将使用增强的整个基因组测序来确定TP53野生型患者是否具有 复发性的非生物突变，以及是否在复发时获得复发突变，而不论TP53如何 地位。我们将与RNA-Seq整合整个基因组Bisulfite测序 引起DNA降压甲基化的特定和规范模式，这些变化是否导致一致 转录特征以及这些模式中的任何一种是否与临床结果相关。