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，这对于 白血病的发展和生存为治疗干预提供了令人兴奋的新机会。 具体来说，组蛋白的甲基化或乙酰化维持了基因表达所需的程序 白血病细胞增殖和存活。该项目的中心假设是小分子 组蛋白修饰抑制剂将有效靶向急性淋巴细胞白血病（ALL）细胞。 我们将通过使用新型小分子、化学生物学方法、新型小鼠来评估这一点 模型和遗传筛选。在具体目标 1 中，我们将努力确定 D0T1L 抑制在 MLL-中的作用 通过对具有显着选择性的有效、特异性 D0T1L 抑制剂进行表征，重排了 ALL 对 MLL 重排 ALL 细胞具有抗增殖和促凋亡作用。在目标 2 中，我们将开发检测方法并 使用新颖的化学方法高通量鉴定新型小分子 DOT1L 抑制剂。在 具体目标 3 我们将合作制定组蛋白脱乙酰酶 (HDAC) 临床开发的基本原理 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 抑制剂和促凋亡分子以及倍性的合理组合 特定药物，并评估特定 HDAC1 和 HDAC2 抑制剂作为潜在的 ALL 导向疗法。 根据临床前数据，我们将评估 HDAC 抑制剂在复发性 ALL 中的作用。我们期望这些目标能够带来 为诊断患有 ALL 的儿童和成人提供更有效、毒性更小的新疗法。 相关性（参见说明）： 虽然儿童急性淋巴细胞白血病 (ALL) 的治疗已取得进展， 被诊断患有携带 MLL 重排的 ALL 的儿童继续表现不佳。此外，特定子集 被诊断患有 ALL 的儿童和大多数成人的预后仍然不佳。在这个项目中我们将 表征靶向 D0T1L 的新小分子，D0T1L 是一种对生存至关重要的组蛋白甲基转移酶 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 开发了 HDAC1/HDAC2 特异性抑制剂作为针对 ALL 细胞的潜在疗法。