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）：这份K24申请支持了我在患者导向研究和指导方面的职业发展。最初的拨款主要用于临床研究，使用新的药物，这些药物被认为是针对癌症中表观遗传介导的异常基因转录。其中包括一项I期研究，将DNA甲基转移酶抑制剂5-氮杂胞苷（5AC）与口服组蛋白去乙酰化酶（HDAC）抑制剂恩替他联合用于骨髓增生异常综合征（MDS）和急性髓性白血病（AML）患者；在复发或高风险AML患者中，两种方案的HDAC抑制剂伏立诺他的随机II期试验；以及一项美国白血病组间随机II期试验（E1905），比较5AC/entinostat联合治疗与5AC单独治疗MDS、慢性髓细胞白血病和AML伴三龄发育不良（MDS相关，AML- tld）。这些研究与旨在剖析这些“表观遗传靶向”药物发挥其临床活性的机制的密集相关实验室科学一起，为生物驱动药物开发的博士生和博士后博士生提供了密集指导的肥沃土壤。这份续期申请需要额外的五年资金来继续我在病人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针对血液恶性肿瘤的表观遗传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将HDAC抑制剂添加到DNA甲基转移酶抑制剂的临床益处的主要试验。这些组合是基于体外数据开发的，这些数据表明，通过基因启动子中胞嘧啶的甲基化，沉默的基因可以协同重新表达。相关研究集中在鉴定治疗时DNA甲基组的改变和特征，这与5AC/恩替诺他的临床反应相关。第二个目的是比较依替诺他按顺序给药（按照5AC）而不是目前的重叠时间表给药的临床结果。第三个目的是研究当HDAC抑制剂与DNMT抑制剂同时给予与顺序给药时表观遗传修饰的差异程度