Targeting Epigenomics in Myeloid Neoplasms

髓系肿瘤的表观基因组靶向

• 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
• 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

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）：此K24申请支持我在以患者为导向的研究和指导方面的职业发展。最初的赠款专注于使用新药物的临床研究，这些新药物针对癌症中靶向表观遗传介导的异常基因转录。其中包括对DNA甲基转移酶抑制剂5-氮杂替丁（5AC）与口服组蛋白脱乙酰基酶（HDAC）抑制剂肠结合的新型组合的研究。 HDAC抑制剂Vorinostat的两个时间表的随机II期试验，对患有复发或高风险AML的患者；以及一项全国性美国白血病间随机II期试验（E1905），将5AC/Entinostat组合与单独的5AC进行比较，以治疗MDS，慢性脊髓细胞性白血病和AML与三肾上腺素增生（MDS相关，AML-TLD）。加上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，这些研究是为生物学驱动药物开发的强化指导前和博士后学员的肥沃基础。该更新申请要求额外的五年资金继续我在以患者为导向的研究和指导中发展的资金，因为我继续在约翰·霍普金斯（Johns Hopkins）和全国范围内在血液学恶性肿瘤中建立综合计划的综合计划，并在霍普金斯（Hopkins）和其他机构中提高我的能力，并提高我的能力，并提高我的指导。 涉及受训者的研究包括与E1905相关的相关科学，这是第一个重大试验，旨在评估将HDAC抑制剂添加到DNA甲基转移酶抑制剂中的临床益处。这些组合是基于体外数据开发的，该数据表明，通过基因启动子中细胞质的甲基化沉默的基因的协同表达。相关研究的重点是在治疗后鉴定DNA甲基体中的改变和特征，这与对5AC/Entinostat的临床反应相关。第二个目的将比较当以依次的方式（以下5AC）而不是当前重叠的时间表给出Entinostat时，将比较临床结果。当HDAC抑制剂与DNMT抑制剂与顺序给药相关时，第三个目标将检查表观遗传修饰在多大程度上不同

项目成果

Should elderly patients with higher-risk myelodysplastic syndromes undergo allogeneic hematopoietic stem cell transplantation?

• DOI: 10.1586/17474086.2013.827097
• 发表时间: 2013-10-01
• 期刊: EXPERT REVIEW OF HEMATOLOGY
• 影响因子: 2.8
• 作者: Zeidan, Amer M.;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

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
• 作者: Griffiths, Elizabeth A.;Gore, Steven D.
• 通讯作者: Gore, Steven D.

Myelodysplastic syndromes: where do we go from here?

骨髓增生异常综合征：我们该何去何从？

• 发表时间: 2011
• 期刊: Oncology (Williston Park, N.Y.)
• 作者: Carraway,HettyE;Gore,StevenD
• 通讯作者: Gore,StevenD

Myelodysplastic syndromes: clinical practice guidelines in oncology.

• DOI: 10.6004/jnccn.2013.0104
• 发表时间: 2013-07
• 期刊: Journal of the National Comprehensive Cancer Network : JNCCN
• 作者: Greenberg PL;Attar E;Bennett JM;Bloomfield CD;Borate U;De Castro CM;Deeg HJ;Frankfurt O;Gaensler K;Garcia-Manero G;Gore SD;Head D;Komrokji R;Maness LJ;Millenson M;O'Donnell MR;Shami PJ;Stein BL;Stone RM;Thompson JE;Westervelt P;Wheeler B;Shead DA;Naganuma M
• 通讯作者: Naganuma M