Genomics of AML Prognosis

AML 预后的基因组学

• 批准号: 10663900
• 负责人: Jatinder K. Lamba
• 金额: $ 37.93万
• 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/10663900
• 关键词: Acceleration; Achievement; Acute Myelocytic Leukemia; Adult; Adult Acute Myeloblastic Leukemia; Ara-C; Azacitidine; Biological; Book Chapters; CRISPR/Cas technology; Cell Line; Childhood; Childhood Acute Myeloid Leukemia; Childhood Leukemia; Clinical; Clinical Trials; Collaborations; Combination Drug Therapy; Custom; DNMT3B gene; Data; Daunorubicin; Decitabine; Development; Diagnosis; Disease; Disease Resistance; Enrollment; Environment; Etoposide; Evaluation; Exposure to; Failure; Florida; Foundations; Funding; Gene Expression; Genes; Genetic Transcription; Genomics; In Vitro; International; Knock-out; Legal patent; Leukemic Cell; Methods; Methylation; Molecular; Outcome; Patients; Pediatric Oncology; Pediatric Oncology Group; Pharmaceutical Preparations; Pharmacogenetics; Pharmacology; Procedures; Productivity; Prognosis; Prognostic Factor; Publications; Qualifying; Randomized; Rare Diseases; Recurrent disease; Research; Research Personnel; Resistance; Saint Jude Children' s Research Hospital; Sample Size; Sampling; Site; Statistical Methods; Translating; Translational Research; Translations; Universities; Validation; Variant; Vertebral column; acute myeloid leukemia cell; 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; novel; older patient; pediatric patients; prognostic; prospective; risk stratification; sound; success; 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：急性髓系白血病（AML）是一种异质性疾病，预后不良， 20%的老年患者和只有50 - 65%的儿科患者治愈并存活3年以上， 诊断.尽管如此，AML治疗的标准疗法主要依赖于阿糖胞苷和紫杉醇的强化组合。 C、柔红霉素和依托泊苷（ADE）已超过40年。治疗后复发和耐药疾病 标准治疗（ADE：阿糖胞苷、柔红霉素和依托泊苷）是最常见的临床失败， 治疗这种疾病。应用程序共同PI，Drs. Lamba（药理学）和Pounds（生物统计学家，专门研究 癌症基因组学）已经成功地合作了十多年，以开发方法和发现分子 AML的预后因素在我们最近完成的第二个供资周期中，我们非常富有成效， 科学出版物，53个会议报告，和两个正在申请的专利。我们的第二轮科学研究 这些成就包括开发了一种ara-C SNP评分，可预测白血病细胞内ara-C水平， CTP，ara-C的活跃形式，创新的综合分析程序的发展;规范 与预测到最有趣的统计证据（CC-PROMISE）的相关性， 在罕见疾病小样本量环境中有意义的生物学发现的统计功效;使用CC- 承诺发现DNMT3B甲基化减少和表达增加与更大的 全基因组甲基化负担和更差的预后;将DNMT3B发现转化为对 正在进行的AML 16临床试验中的去甲基化剂;六基因的开发和初步验证 儿科白血病干细胞（pLSC 6）评分（专利申请中）和五基因ADE耐药评分（ADE-RS 5）评分 可以预测预后在这次更新申请中，我们建议通过广泛的 验证pLSC6和ADE-RS5评分，为将其转化为临床应用提供坚实的科学基础。 实践和进一步发展我们对AML发展和预后的生物学基础的理解， 其他分子结构域。在目前的提案中，我们寻求通过广泛验证 10个独立的国家和国际AML队列中约4000例患者的pLSC6和ADE-RS5评分 接受强化化疗，为将其转化为临床实践提供坚实的科学基础。 在目标2中，我们建议进行临床结局-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学特征， 将在目标2中进行彻底的机械验证。这些研究的成功完成将是 通过准备合理的科学依据，纳入预后基因， 表达评分纳入AML患者的风险分层，并揭示了分子基础的其他层面 AML预后，以指导开发更有效的治疗方法。