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Targeting to Epigenetic Modications in ALL

针对 ALL 的表观遗传修饰

基本信息

批准号：
8550799
负责人：
SCOTT A ARMSTRONG
金额：
$ 37.81万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-25 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8550799
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 DNA Sequence Rearrangement 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 Histones 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 cytotoxic design genome-wide high throughput screening 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

项目摘要

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了基因表达所必需的程序，白血病细胞增殖和存活。这个项目的核心假设是，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，新的小鼠模型和基因筛选在具体目标1中，我们将致力于定义D 0 T1 L抑制在MLL中的作用。通过表征具有显著选择性的强效特异性D 0 T1 L抑制剂，对MLL重排的ALL细胞的抗增殖和促凋亡作用。在目标2中，我们将开发检测方法，使用新的化学方法高通量鉴定新的小分子DOT 1 L抑制剂。在具体目标3：我们将致力于开发组蛋白去乙酰化酶（HDAC）临床开发的基本原理抑制剂作为ALL的疗法，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的合理组合以及倍性- 特异性药物，并评估特异性HDAC 1和HDAC 2抑制剂作为潜在的ALL定向治疗剂。基于临床前数据，我们将评估HDAC抑制剂在复发性ALL中的作用。我们预计这些目标将带来新的更有效，毒性更小的治疗方法，用于诊断为ALL的儿童和成人。相关性（见说明）：虽然儿童急性淋巴细胞白血病（ALL）的治疗已经取得了进展，被诊断为ALL的儿童携带MLL重排继续做poody。此外，被诊断为ALL的儿童和大多数成年人的结果仍然很差。在这个项目中，我们将表征靶向D 0 T1 L的新小分子，D 0 T1 L是一种对人类生存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去乙酰化酶（HDAC）抑制剂和新的开发了HDAC 1/HDAC 2特异性抑制剂作为针对ALL细胞的潜在治疗剂。