Targeting Epigenomics in Myeloid Neoplasms

髓系肿瘤的表观基因组靶向

• 批准号: 8045547
• 负责人: STEVEN D GORE
• 金额: $ 19.69万
• 依托单位: JOHNS HOPKINS 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/8045547
• 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 Delivery Systems; 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; 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 PUBLIC HEALTH RELEVANCE: Drugs which target aberrant transcription in cancer through modification of epigenetic marks demonstrate marked activity in myeloid leukemias; however the mechanism by which these drugs improve clinical outcome remains uncertain. Understanding the mechanism underlying clinically activity is critical for development of better drugs, and for the effective development of epigenetically-targeted strategies in other more common cancers.

描述（由申请人提供）：此 K24 申请支持了我在以患者为导向的研究和指导方面的职业发展。最初的资助重点是使用新药物进行临床研究，这些新药物可能针对癌症中表观遗传介导的异常基因转录。其中包括一项针对骨髓增生异常综合征 (MDS) 和急性髓系白血病 (AML) 患者的 DNA 甲基转移酶抑制剂 5-氮杂胞苷 (5AC) 与口服组蛋白脱乙酰酶 (HDAC) 抑制剂恩替司他 (entinostat) 新型组合的 I 期研究；对复发或高危 AML 患者进行 HDAC 抑制剂伏立诺他两种治疗方案的随机 II 期试验；一项美国国家白血病组间随机 II 期试验 (E1905) 比较了 5AC/entinostat 组合与单独 5AC 治疗 MDS、慢性粒单核细胞白血病和伴有三系不典型增生的 AML（MDS 相关，AML-TLD）的疗效。与旨在剖析这些“表观遗传靶向”药物发挥临床活性机制的密集相关实验室科学一起，这些研究为生物驱动药物开发中博士前和博士后学员的强化指导提供了沃土。此续签申请要求额外五年的资金，以继续我在以患者为导向的研究和指导方面的发展，因为我将继续在约翰·霍普金斯大学和全国范围内建立血液恶性肿瘤表观遗传学靶向药物开发的综合项目，并提高我作为霍普金斯大学和其他机构更多初级教师的导师的能力和影响力。 学员将参与的研究包括与 E1905 相关的相关科学，这是第一个严格评估在 DNA 甲基转移酶抑制剂中添加 HDAC 抑制剂的临床益处的重大试验。这些组合是基于体外数据开发的，这些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重新表达。相关研究的重点是识别治疗后 DNA 甲基化组的改变和特征，这与 5AC/entinostat 的临床反应相关。第二个目标是比较以顺序方式（遵循 5AC）而不是当前重叠的时间表给予恩替司他时的临床结果。第三个目标是检查 HDAC 抑制剂与 DNMT 抑制剂同时给药与序贯给药时表观遗传修饰的差异程度 公共健康相关性：通过修饰表观遗传标记来靶向癌症中的异常转录的药物在骨髓性白血病中表现出显着的活性；然而，这些药物改善临床结果的机制仍不确定。了解临床活性的机制对于开发更好的药物以及在其他更常见的癌症中有效开发表观遗传学靶向策略至关重要。