Genomics of AML Prognosis

AML 预后的基因组学

• 批准号: 10747046
• 负责人: Jatinder K. Lamba
• 金额: $ 7.98万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747046
• 关键词: Acceleration; Achievement; Acute Myelocytic Leukemia; Ara-C; Biological; Childhood Leukemia; Clinical; Clinical Trials; Collaborations; DNMT3B gene; Daunorubicin; Development; Diagnosis; Disease; Disease Resistance; Etoposide; Evaluation; Failure; Foundations; Funding; Gene Expression; Genes; Genomics; International; Legal patent; Leukemic Cell; Methods; Methylation; Molecular; Outcome; Patients; Pharmacology; Procedures; Productivity; Prognosis; Prognostic Factor; Publications; Rare Diseases; Recurrent disease; Research; Resistance; Sample Size; Translating; Translations; Validation; Variant; cancer genomics; chemotherapy; clinical practice; clinically significant; cohort; demethylation; effective therapy; epigenomics; genome wide association study; genome wide methylation; innovation; leukemia treatment; leukemic stem cell; molecular domain; older patient; pediatric patients; prognostic; risk stratification; sound; symposium; transcriptomics; Acceleration; Achievement; Acute Myelocytic Leukemia; Ara-C; Biological; Childhood Leukemia; Clinical; Clinical Trials; Collaborations; DNMT3B gene; Daunorubicin; Development; Diagnosis; Disease; Disease Resistance; Etoposide; Evaluation; Failure; Foundations; Funding; Gene Expression; Genes; Genomics; International; Legal patent; Leukemic Cell; Methods; Methylation; Molecular; Outcome; Patients; Pharmacology; Procedures; Productivity; Prognosis; Prognostic Factor; Publications; Rare Diseases; Recurrent disease; Research; Resistance; Sample Size; Translating; Translations; Validation; Variant; cancer genomics; chemotherapy; clinical practice; clinically significant; cohort; demethylation; effective therapy; epigenomics; genome wide association study; genome wide methylation; innovation; leukemia treatment; leukemic stem cell; molecular domain; older patient; pediatric patients; prognostic; risk stratification; sound; symposium; transcriptomics

1. ABSTRACT: Acute Myeloid Leukemia (AML) is a heterogeneous disease with a dismal outcome; fewer than 20% of elderly patients and only 50-65% of pediatric patients are cured and survive more than 3 years following diagnosis. Despite this, the standard therapy for AML treatment has relied primarily on an intensive combination of ara- C, daunorubicin, and etoposide (ADE) for over 40 years. Relapsed and resistant disease following treatment with standard therapy (ADE: ara-C, daunorubicin, and etoposide) are the most common clinical failures that occur in treating this disease. Application co-PIs, Drs. Lamba (pharmacology) and Pounds (biostatistician specializing in cancer genomics) have successfully collaborated for over a decade to develop methods and discover molecular prognostic factors for AML. During our recently completed second funding cycle, we were very productive with 13 scientific publications, 53 conference presentations, and two pending patents. Our second-cycle scientific achievements include the development of an ara-C SNP score that predicts leukemic cell intracellular levels of ara- CTP, the active form of ara-C the development of the innovative integrative analysis procedure; canonical correlation with projection onto the most interesting statistical evidence (CC-PROMISE), that dramatically increases statistical power for meaningful biological discovery in a rare-disease small sample size setting; using CC- PROMISE to discover that reduced methylation and increased expression of the DNMT3B associates with greater genome-wide methylation burden and worse prognosis; translating the DNMT3B discovery into evaluation of demethylating agents in the ongoing AML16 clinical trial; the development and initial validation of the six-gene pediatric leukemia stem cell (pLSC6) score (patent pending) and five-gene ADE resistance score (ADE-RS5) score that predict prognosis. In this renewal application, we propose to accelerate our exciting progress by extensively validating the pLSC6 and ADE-RS5 scores to provide a robust scientific foundation to translate them into clinical practice and further developing our understanding of the biological basis of AML development and prognosis into other molecular domains. In the current proposal we seek to accelerate our exciting progress by extensively validating the pLSC6 and ADE-RS5 scores in ~ 4000 patients across 10 independent national and international AML cohorts treated on intensive chemotherapy, to provide a robust scientific foundation for its translation into clinical practice. In aim 2, we propose to perform a clinical outcome-GWAS (CO-GWAS) and establish prognostic genes and variants with a constellation of genomic, epigenomic, and transcriptomic features that associate with clinical outcomes which will undergo thorough mechanistic validation in aim 2. The successful completion of these studies will be scientifically and clinically significant by preparing a sound scientific rationale to incorporate prognostic gene expression scores into the risk stratification of AML patients and revealing additional layers of the molecular basis of AML prognosis to guide the development of more effective therapies.

1。摘要：急性髓样白血病（AML）是一种异质疾病，结果令人沮丧。比 20％的老年患者和只有50-65％的小儿患者治愈并在3年之后生存 诊断。尽管如此，AML治疗的标准疗法主要依赖于ARA-的密集型组合 C，daunorubicin和依托泊苷（ADE）已有40多年了。治疗后，复发和抗性疾病 标准疗法（ADE：ARA-C，Daunorubicin和Etoposide）是最常见的临床失败 治疗这种疾病。应用程序Co-Pis，Drs。 Lamba（药理学）和磅（Biostatisticians 癌症基因组学）已经成功合作了十多年，以开发方法并发现分子 AML的预后因素。在我们最近完成的第二个融资周期中，我们非常有生产力，有13个 科学出版物，53次会议演讲和两项悬而未决的专利。我们的第二周期科学 成就包括发展ARA-C SNP评分，该评分预测白血病细胞内Ara-的细胞内水平 CTP，ARA-C的主动形式是创新综合分析程序的开发；典范 与预测到最有趣的统计证据（CC促销）的相关性，该证据大大增加了 在稀有疾病中，有意义的生物学发现的统计能力小样本量设置；使用CC- 承诺发现甲基化降低并增加了DNMT3B联合的表达 全基因组甲基化负担和预后较差；将DNMT3B发现转化为评估 正在进行的AML16临床试验中的脱甲基剂；六基因的开发和初步验证 小儿白血病干细胞（PLSC6）评分（申请专利）和五基因ADE阻力评分（ADE-RS5）得分 这可以预测预后。在此续签应用中，我们建议通过广泛的 验证PLSC6和ADE-RS5分数以提供强大的科学基础，以将其转化为临床 实践并进一步发展我们对AML发展和预后生物学基础的理解 其他分子结构域。在当前的建议中，我们试图通过广泛的验证来加速激动人心的进步 在10名独立国家和国际AML队列中，PLSC6和ADE-RS5在约4000名患者中得分 接受强化化疗的治疗，为将其转化为临床实践提供了强大的科学基础。 在AIM 2中，我们建议执行临床结果GWAS（Co-GWAS）并建立预后基因和变体 具有与临床结果相关的基因组，表观基因组和转录组特征的星座 AIM 2将经过彻底的机械验证。这些研究的成功完成将是 通过准备合理的科学原理以纳入预后基因，以科学和临床上的意义 表达评分为AML患者的风险分层，并揭示了分子基础的其他层 AML预后指导更有效疗法的发展。