Genome-wide Identification of DNA Methylation Biomarkers in AML

AML 中 DNA 甲基化生物标志物的全基因组鉴定

• 批准号: 8517043
• 负责人: Joseph Michael Scandura
• 金额: $ 14.52万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517043
• 关键词: Acute Myelocytic Leukemia; Address; Adult; Adult Acute Myeloblastic Leukemia; Affect; Azacitidine; Back; Basic Science; Binding; Biological; Biological Markers; Blood; Blood Cells; Blood specimen; Bone Marrow; CD34 gene; Cataloging; Catalogs; Cell Differentiation process; Cells; Characteristics; Clinical; Clinical Trials; Clinical Trials Design; Collection; Complement; DNA; DNA Methylation; Data; Decitabine; Deoxycytidine; Development; Dose; Dysmyelopoietic Syndromes; Elements; Epigenetic Process; Future; Genetic Risk; Genomics; Goals; Hand; Health; Hematopoietic; Human; Lead; Lesion; Link; Lymphocyte; Malignant Neoplasms; Measures; Memorial Sloan-Kettering Cancer Center; Methods; Mission; Monitor; Mononuclear; Motivation; Outcome; Patients; Pattern; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Population; Public Health; Publishing; Recurrence; Regimen; Relapse; Reporting; Research; Research Design; Research Support; Residual Neoplasm; Resistance; Risk; Schedule; Specimen; Staging; Stem cells; Testing; Tissues; Toxic effect; Treatment Protocols; Tumor Suppressor Genes; United States National Institutes of Health; Validation; Work; base; cancer therapy; cell type; chemotherapy; clinical application; effective therapy; genome wide association study; genome-wide; improved; in vivo; innovation; leukemia; leukemic stem cell; medical schools; monocyte; older patient; peripheral blood; response; standard measure; stem; translational study

DESCRIPTION (provided by applicant): DNA hypomethylating agents (HMA) promise to significantly advance the treatment of acute myelogenous leukemia (AML). The drugs are well tolerated in older patients who represent both the majority of adult AML, and those least well served by traditional, intensive chemotherapy. The dose and delivery schedule of HMAs strongly dictate biological activity but the pharmacodynamics of these agents is poorly understood. The absence of good biomarkers of DNA methylation is slowing the development of epigenetic therapy in AML. The long-term goal of this research is to develop effective and well-tolerated AML therapies that incorporate optimally dosed epigenetic modifiers. The objective of this application is to identify DNA methylation biomarkers that can be used to assess the activity of HMAs in AML leukemia stem/progenitor cells (LSPCs). The central hypothesis is that pharmacodynamic biomarkers of HMA activity have greatest clinical/biological relevance when they report efficacy within AML LSPCs. The rationale for the proposed studies is that, once AML-specific DNA methylation abnormalities are discovered, they can be used to assess the pharmacodynamic activity of HMAs in clinical trials designed to optimize the dose and delivery schedule of these agents for the treatment of AML. The hypothesis will be tested by pursuing two specific aims: Aim 1: Identify DNA methylation biomarkers of AML. Aim 2: Determine whether peripheral blood cells can be used as a surrogate tissue to assess decitabine-induced DNA hypomethylation in AML LSPCs. Under the first aim, a proven method for genome-wide analyses of DNA methylation that has already been established to be feasible in the applicants' hands, will be used to identify AML-specific abnormalities in CD34-selected primary, human AML LSPCs when compared to normal hematopoietic cells obtained from healthy donors. The second aim will use previously collected, matched blood and bone marrow specimens obtained from patients with AML prior to and immediately following, several different decitabine administration schedules to identify AML-specific DNA methylation biomarkers suitable for pharmacodynamic monitoring in peripheral blood cells. These results are expected to have a positive impact on the clinical development of current and future DNA hypomethylating agents by providing a long sought after means to assess the biological activity of these agents in vivo. This contribution is significant be- cause it is a necessary first step in a continuum of research that is expected to yield pharmacodynamically tailored dosing of epigenetic modifiers that maximize anti-leukemic activity while minimizing toxicity. The pro- posed research is innovative because it represents a substantial departure from the current standard of measuring DNA methylation at a few convenient genomic loci in mixed cell populations long-after the delivery of a DNA HMA. Ultimately, the proposed genome-wide identification of AML-specific DNA methylation biomarkers in LSPCs and validation of celular surrogates with which to assess pharmacodynamics should permit rapid optimization, and perhaps personalization, of HMA schedules for the treatment of AML.

描述（由申请人提供）：DNA低甲基化剂（HMA）有望显着推进急性髓性白血病（AML）的治疗。这些药物在老年患者中耐受性良好，这些患者代表了大多数成人AML，以及传统强化化疗效果最差的患者。HMA的剂量和给药方案强烈决定了生物活性，但对这些药物的药效学了解甚少。缺乏良好的DNA甲基化生物标志物正在减缓AML表观遗传治疗的发展。这项研究的长期目标是开发有效和耐受性良好的AML疗法，其中包括最佳剂量的表观遗传修饰剂。本申请的目的是鉴定可用于评估AML白血病干/祖细胞（LSPC）中HMA活性的DNA甲基化生物标志物。中心假设是HMA活性的药效学生物标志物在AML LSPC中报告疗效时具有最大的临床/生物学相关性。拟议研究的基本原理是，一旦发现AML特异性DNA甲基化异常，它们可用于评估临床试验中HMA的药效学活性，旨在优化这些药物治疗AML的剂量和给药方案。该假设将通过追求两个具体目标进行测试：目标1：确定AML的DNA甲基化生物标志物。目的2：确定外周血细胞是否可以用作替代组织，以评估AML LSPC中地西他滨诱导的DNA低甲基化。在第一个目标下，已经确定在申请人手中可行的用于DNA甲基化的全基因组分析的经证实的方法将用于在与从健康供体获得的正常造血细胞相比时鉴定CD 34选择的原代人AML LSPC中的AML特异性异常。第二个目标将使用先前收集的、匹配的血液和骨髓标本，这些标本是在几种不同的地西他滨给药方案之前和之后立即从AML患者中获得的，以鉴定适合于外周血细胞中药效学监测的AML特异性DNA甲基化生物标志物。这些结果预计将对目前和未来的DNA低甲基化剂的临床开发产生积极影响，因为它提供了一种长期寻求的方法来评估这些药物在体内的生物活性。这一贡献是重要的，因为它是连续研究中必要的第一步，该连续研究预期产生药效学定制的表观遗传修饰剂剂量，其最大化抗白血病活性，同时最小化毒性。所提出的研究是创新的，因为它代表了在递送DNA HMA很长时间后在混合细胞群体中的几个方便的基因组基因座处测量DNA甲基化的当前标准的实质性偏离。最终，拟议的全基因组鉴定LSPC中AML特异性DNA甲基化生物标志物和验证用于评估药效学的细胞替代物应允许快速优化，甚至个性化HMA治疗AML的时间表。

项目成果

Phase I Study of Epigenetic Priming with Azacitidine Prior to Standard Neoadjuvant Chemotherapy for Patients with Resectable Gastric and Esophageal Adenocarcinoma: Evidence of Tumor Hypomethylation as an Indicator of Major Histopathologic Response.

• DOI: 10.1158/1078-0432.ccr-16-1896
• 发表时间: 2017-06-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Schneider BJ;Shah MA;Klute K;Ocean A;Popa E;Altorki N;Lieberman M;Schreiner A;Yantiss R;Christos PJ;Palmer R;You D;Viale A;Kermani P;Scandura JM
• 通讯作者: Scandura JM