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.

项目总结