Targeting to Epigenetic Modications in ALL

针对 ALL 的表观遗传修饰

• 批准号: 8916649
• 负责人: SCOTT A ARMSTRONG
• 金额: $ 40.23万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-25 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916649
• 关键词: Acute Lymphocytic Leukemia; Adult; Aftercare; Biochemical; Biological; Biological Assay; Cell Line; Cell Proliferation; Cell Survival; Cells; Cellular Assay; Chemicals; Child; Childhood Acute Lymphocytic Leukemia; Clinical; Clinical Trials; Complex; Cytotoxic Chemotherapy; Data; Development; Diagnosis; Disease; Doctor of Medicine; Doctor of Philosophy; Drug Kinetics; Epigenetic Process; Funding; Future; Gene Expression; Genes; Genetic Screening; HDAC1 gene; HDAC2 gene; Histone Acetylation; Histone Deacetylase Inhibitor; Human; In Vitro; Lead; Libraries; Methylation; Modeling; Mus; Outcome; Patients; Ploidies; Preclinical Testing; Principal Investigator; Property; RNA Interference; Relapse; Role; Structure; Therapeutic; Therapeutic Intervention; Translating; Translations; Work; Xenograft Model; Xenograft procedure; assay development; base; chemotherapeutic agent; chemotherapy; clinical investigation; cytotoxic; design; genome-wide; high throughput screening; histone methylation; histone methyltransferase; histone modification; human disease; in vivo; inhibitor/antagonist; leukemia; member; mouse model; novel; novel strategies; pre-clinical; programs; prototype; research clinical testing; response; screening; small hairpin RNA; small molecule; therapeutic target

Increased understanding ofthe epigenetic mechanisms that control gene expression programs important for leukemia development and survival provides exciting new opportunities for therapeutic intervention. Specifically, methylation or acetylation of histones maintains gene expression programs necessary for leukemia cell proliferation and survival. The central hypothesis for this project is that small molecule inhibitors of histone modifications will effectively target acute lymphoblastic leukemia (ALL) cells. We will assess this through the use novel small molecules, chemical biological approaches, novel mouse models and genetic screens. In specific aim 1 we will work to define a role for D0T1L inhibition in MLL- Rearranged ALL through characterization of a potent, specific D0T1L inhibitor that has remarkably selective anti-proliferative and proapoptotic effects on MLL-rearranged ALL cells. In aim 2 we will develop assays and use novel chemical approaches for high-throughput identification of new small molecule DOT1L inhibitors. In specific aim 3 we will work with to develop rationale for clinical development of histone deacetylase (HDAC) inhibitors as therapies for ALL, with a particular focus on leukemias that result in high end-induction MRD. We will also determine rational combinations of HDAC inhibitors and proapototic molecules and with ploidy- specific agents, and evaluate specific HDAC1 and HDAC2 inhibitors as potential ALL-directed therapeutics. Based on preclinical data, we will assess HDAC inhibitors in relapsed ALL. We expect these aims to bring new more efficacious, less toxic therapies to children and adults diagnosed with ALL. RELEVANCE (See instmctions): While improvements have been made in the treatment of childhood acute lymphoblastic leukemia (ALL), children diagnosed with ALL harboring MLL-rearrangements continue to do poody. Also, specific subsets of children and most adults diagnosed with ALL continue to have poor outcomes. In this project we will characterize new small molecules that target D0T1L, a histone methyltransferase important for survival of yWLL-rearranged leukemias. We will also assess both pan-histone deacetylase (HDAC) inhibitors and newly developed HDAC1/HDAC2 specific inhibitors as potential therapeutics against ALL cells.

增加对控制基因表达程序的表观遗传机制的理解 白血病的发展和存活为治疗干预提供了令人兴奋的新机会。 具体地说，组蛋白的甲基化或乙酰化维持着必要的基因表达程序 白血病细胞的增殖和存活。这个项目的中心假设是小分子 组蛋白修饰的抑制剂将有效地靶向急性淋巴细胞白血病(ALL)细胞。 我们将通过使用新的小分子、化学生物学方法、新的小鼠来评估这一点 模特和基因筛查。在具体目标1中，我们将努力定义D0T1L抑制在MLL中的作用- 对一种有效的、特异的D0T1L抑制剂进行了全程重排，该抑制剂具有显著的选择性 MLL重排ALL细胞的抗增殖和促凋亡作用。在目标2中，我们将开发分析方法和 使用新的化学方法高通量鉴定新的小分子DOT1L抑制剂。在……里面 具体目标3我们将致力于为组蛋白脱乙酰酶(Hdac)的临床开发提供理论基础。 抑制剂作为ALL的治疗方法，特别关注导致高端诱导MRD的白血病。 我们还将确定HDAC抑制剂和细胞凋亡原分子的合理组合以及倍性- 特定的药物，并评估特定的HDAC1和HDAC2抑制剂作为潜在的全定向治疗。 基于临床前数据，我们将评估复发急性淋巴细胞白血病的HDAC抑制剂。我们预计这些目标将带来 新的更有效、毒性更低的治疗方法，适用于诊断为ALL的儿童和成人。 相关性(请参阅说明)： 虽然在儿童急性淋巴细胞性白血病(ALL)的治疗方面取得了改进， 被诊断为所有存在MLL重排的儿童继续表现为POODY。此外，特定的子集 被诊断为ALL的儿童和大多数成年人的预后仍然很差。在这个项目中，我们将 鉴定靶向D0T1L的新小分子，D0T1L是组蛋白甲基转移酶，对猪的生存至关重要 YWLL-重排白血病。我们还将评估泛组蛋白脱乙酰酶(HDAC)抑制剂和新的 开发HDAC1/HDAC2特异性抑制剂作为潜在的治疗ALL细胞的药物。