Project 1 - Molecular Determinants of Decitabine Responses.

项目 1 - 地西他滨反应的分子决定因素。

基本信息

批准号：
10439621
负责人：
TIMOTHY J. LEY
金额：
$ 32.92万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-03 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10439621
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 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

项目摘要

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.

项目概要该项目的长期目标是确定患有急性髓系白血病 (AML) 的患者最有可能对地西他滨治疗产生反应，并确定其分子机制地西他滨反应。我们最近报道了 TP53 突变的 AML 和 MDS 患者，这些患者具有较高的复发风险和非常差的结果，对地西他滨持续有效，地西他滨是一种低甲基化药物，可以作为门诊患者给予，大多数患者耐受性良好。然而，大多数有反应的患者没有 TP53 突变，表明其他途径也可以影响地西他滨敏感性。这目前尚不清楚与地西他滨反应和随后的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标：目标 1. 我们将确定地西他滨挽救治疗对 TP53 的 AML 患者的疗效突变。患有复发/难治性 AML 且具有 TP53 突变的患者是超高风险人群预后极差的人群，代表治疗需求未得到满足。因此，我们将治疗 60 已知有 TP53 突变的复发/难治性 AML 患者在 28 天周期的第 1-10 天接受地西他滨治疗三个中心（华盛顿大学、弗雷德·哈钦森癌症研究中心和爱荷华大学）。如果可能的话，有反应的患者将接受同种异体移植以进行巩固治疗。我们将确定 1 年总生存率、反应率、移植时间、白血病复发时间，以及第 1 周期和第 2 周期期间的平均住院天数。目标 2. 我们将定义与地西他滨反应相关的基因组和表观基因组特征。我们将使用增强型全基因组测序来确定 TP53 野生型患者是否患有复发性非基因突变，以及复发时是否获得复发性突变，与 TP53 无关地位。我们将把全基因组亚硫酸氢盐测序与 RNA-Seq 相结合，以确定地西他滨是否导致 DNA 低甲基化的特定和规范模式，这些变化是否会导致一致的结果转录特征，以及这些模式是否与临床结果相关。