Targeting Epigenomics in Myeloid Neoplasms

髓系肿瘤的表观基因组靶向

• 批准号: 8688921
• 负责人: STEVEN D GORE
• 金额: $ 19.71万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-08 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8688921
• 关键词: Acute Myelocytic Leukemia; Applications Grants; Azacitidine; Biological; Cancer Center; Cell Proliferation; Cells; Chronic Myelomonocytic Leukemia; Classification; Clinical; Clinical Research; Correlative Study; Cytosine; DNA; DNA Methyltransferase Inhibitor; DNA biosynthesis; Data; Databases; Development; Dose; Drug Administration Schedule; Drug Combinations; Drug Targeting; Dysmyelopoietic Syndromes; Dysplasia; Epigenetic Process; Faculty; Funding; Future; Gene Silencing; Genes; Genetic Transcription; Grant; Hematologic Neoplasms; Histone Deacetylase Inhibitor; Histones; Human; In Vitro; Institution; Laboratories; Leadership; MS-275; Malignant Neoplasms; Mediating; Mentors; Methylation; Modification; Myeloid Leukemia; Myeloproliferative disease; New Agents; Oral; Outcome; Patient Selection; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phase II Clinical Trials; Postdoctoral Fellow; Protocols documentation; Randomized; Relapse; Request for Applications; Research; Resistance; S Phase; Sampling; Schedule; Science; System; Translational Research; United States National Institutes of Health; Validation; Vorinostat; base; cancer cell; career development; comparative; comparative efficacy; design; drug development; epigenomics; high risk; improved; inhibitor/antagonist; leukemia; methylome; novel; older patient; patient oriented research; phase 1 study; pre-doctoral; programs; promoter; response; translational study; trial comparing

DESCRIPTION (provided by applicant): This K24 application has supported my career development in patient oriented research and mentoring. The original grant focused on clinical studies using new agents which putatively target epigenetically-mediated aberrant gene transcription in cancer. These included a Phase I study of a novel combination of the DNA methyltransferase inhibitor 5-azacytidine (5AC) with an oral histone deacetylase (HDAC) inhibitor entinostat in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML); a randomized Phase II trial of two schedules of the HDAC inhibitor vorinostat in patients with relapsed or high risk AML; and a national US Leukemia Intergroup randomized Phase II trial (E1905) comparing the 5AC/entinostat combination to 5AC alone for the treatment of MDS, chronic myelomonocytic leukemia, and AML with trilineage dysplasia (MDS-associated, AML-TLD). Together with intensive correlative laboratory science aimed at dissecting the mechanisms by which these "epigenetically targeted" drugs exert their clinical activity, these studies have been fertile ground for intensive mentoring of pre- and post-doctoral trainees in biologically-driven drug development. This renewal application requests an additional five years of funding to continue my development in patient oriented research and mentoring as I continue to build integrated programs in epigenetically targeted drug development in hematologic malignancies at Johns Hopkins and nationally, and increase my abilities and reach as a mentor to more junior faculty at Hopkins and at other institutions. The research in which mentees will be involved includes the correlative science associated with E1905, which is the first major trial to critically assess the clinical benefit of the addition of an HDAC inhibitor to a DNA methyltransferase inhibitor. These combinations have been developed based on in vitro data demonstrating synergistic re-expression of genes silenced through methylation of cytosines in gene promoters. The correlative studies focus on identifying alterations and signatures in the DNA methylome upon treatment, which correlate with clinical response to 5AC/entinostat. The second aim will compare clinical outcomes when entinostat is given in a sequential manner (following 5AC) rather than the current overlapping schedule. The third aim will examine to what extent epigenetic modifications differ when the HDAC inhibitor is given concomitantly with the DNMT inhibitor versus sequential administration

描述(由申请者提供)：这份K24申请表支持了我在以病人为中心的研究和指导方面的职业发展。最初的拨款集中于使用新的药物进行临床研究，这些药物可能针对表观遗传介导的癌症异常基因转录。这些研究包括：DNA甲基转移酶抑制剂5-氮胞苷(5AC)和口服组蛋白去乙酰酶(HDAC)抑制剂Eninostat的新组合用于骨髓增生异常综合征(MDS)和急性髓细胞白血病(AML)患者的新组合的I期研究；HDAC抑制剂voinostat两个疗程的随机II期试验，用于复发或高危AML患者；美国全国白血病组间随机II期试验(E1905)，比较5AC/Eninostat联合和5AC单独治疗MDS、慢性粒单核细胞白血病和AML伴有三系发育不良(MDS相关的AML-TLD)的疗效。这些研究与旨在剖析这些“表观基因靶向”药物发挥临床活性的机制的密集相关实验室科学一起，为在生物驱动的药物开发方面对博士后和博士后实习生进行密集指导提供了肥沃的土壤。这份续签申请要求额外的五年资金，以继续我在以患者为导向的研究和指导方面的发展，同时我继续在约翰·霍普金斯大学和全国范围内建立表观遗传靶向恶性血液病药物开发的综合计划，并提高我的能力，作为霍普金斯大学和其他机构更初级的教师的导师。受试者将参与的研究包括与E1905相关的科学，这是第一个严格评估在DNA甲基转移酶抑制剂的基础上添加HDAC抑制剂的临床益处的主要试验。这些组合是基于体外数据，证明了通过基因启动子中胞嘧啶甲基化而沉默的基因的协同再表达。相关研究的重点是确定治疗后DNA甲基组的改变和信号，这些变化和信号与临床对5AC/恩替诺斯特的反应有关。第二个目标是比较按顺序(遵循5AC)而不是目前重叠的时间表给予内抑素时的临床结果。第三个目的将检验当HDAC抑制剂与DNMT抑制剂同时给药与顺序给药时，表观遗传修饰的不同程度