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Targeting Epigenomics in Myeloid Neoplasms

髓系肿瘤的表观基因组靶向

基本信息

批准号：
8907913
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
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-08 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8907913
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 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 phase I trial phase II trial pre-doctoral programs promoter response translational study trial comparing

项目摘要

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（由申请人提供）：这个K24应用程序支持我的职业发展，以病人为导向的研究和指导。最初的拨款集中在使用新药物的临床研究，这些药物可以靶向癌症中表观遗传介导的异常基因转录。这些包括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）抑制剂恩替司他的新型组合在骨髓增生异常综合征（MDS）和急性髓性白血病（AML）患者中的I期研究; HDAC抑制剂伏立诺他的两种方案在复发或高危AML患者中的随机II期试验;以及一项美国国家白血病组间随机II期试验（E1905），比较了5AC/恩替司他组合与单独5AC用于治疗MDS、慢性粒单核细胞白血病和伴有三系发育不良的AML（MDS相关，AML-AML）。连同密集的相关实验室科学，旨在解剖这些“表观遗传靶向”药物发挥其临床活性的机制，这些研究一直是密集的指导前和博士后学员在生物驱动的药物开发肥沃的土壤。这一更新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的发展，因为我继续在约翰霍普金斯和全国建立血液恶性肿瘤表观遗传靶向药物开发的综合计划，并提高我的能力和作为导师在霍普金斯和其他机构的更多初级教师的影响力。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，这些数据表明通过基因启动子中胞嘧啶的甲基化沉默的基因的协同再表达。相关研究的重点是识别治疗后DNA甲基化组的改变和特征，这些改变和特征与对5AC/恩替司他的临床应答相关。第二个目的是比较恩替司他以序贯方式（在5AC之后）而不是当前重叠时间表给予时的临床结果。第三个目的是检查HDAC抑制剂与DNMT抑制剂同时给药与顺序给药时，表观遗传修饰的差异程度

项目成果

期刊论文数量（64）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Treatment of acute promyelocytic leukemia for older patients.

DOI：
10.6004/jnccn.2011.0030
发表时间：
2011-03
期刊：
Journal of the National Comprehensive Cancer Network : JNCCN
影响因子：
0
作者：
Prebet T;Gore SD
通讯作者：
Gore SD

In vitro basis for treatment with hypomethylating agents and histone deacetylase inhibitors: can epigenetic changes be used to monitor treatment?

低甲基化药物和组蛋白脱乙酰酶抑制剂治疗的体外基础：表观遗传变化能否用于监测治疗？

DOI：
10.1016/s0145-2126(09)70226-7
发表时间：
2009
期刊：
Leukemia research
影响因子：
2.7
作者：
Gore,StevenD
通讯作者：
Gore,StevenD

Myelodysplastic syndromes: where do we go from here?

骨髓增生异常综合征：我们该何去何从？

DOI：
发表时间：
2011
期刊：
Oncology (Williston Park, N.Y.)
影响因子：
0
作者：
Carraway,HettyE;Gore,StevenD
通讯作者：
Gore,StevenD

Epigenetic therapies in MDS and AML.

DOI：
10.1007/978-1-4419-9967-2_13
发表时间：
2013
期刊：
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
影响因子：
0
作者：
Griffiths, Elizabeth A.;Gore, Steven D.
通讯作者：
Gore, Steven D.

Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes.

DOI：
10.1038/leu.2015.265
发表时间：
2016-04
期刊：
Leukemia
影响因子：
11.4
作者：
Garcia-Manero G;Gore SD;Kambhampati S;Scott B;Tefferi A;Cogle CR;Edenfield WJ;Hetzer J;Kumar K;Laille E;Shi T;MacBeth KJ;Skikne B
通讯作者：
Skikne B