Epigenetics and Epigenetic Therapy in AML

AML 的表观遗传学和表观遗传学治疗

基本信息

批准号：
8499744
负责人：
HAGOP KANTARJIAN
金额：
$ 89.97万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8499744
关键词：
Affect Antifungal Agents Applications Grants Area Arsenic Trioxide Azacitidine Binding Binding Proteins Ca(2+)-Calmodulin Dependent Protein Kinase Calcium Calcium Signaling Cancer Biology Carboplatin Cardiac Cardiac Glycosides Cells Chemical Structure Chromatin Clinical Trials DNA Damage DNA Methylation DNMT3a Data Decitabine Dependence Development Digoxin Disease Disulfiram Drug Combinations Embryonic Development Ensure Epigenetic Process Essential Genes FDA approved Funding Gene Activation Gene Expression Gene Silencing Genes Genomics Grant Hematologic Neoplasms Histone Deacetylase Inhibitor Instruction Lead Leukemic Cell Libraries Malignant - descriptor Malignant Neoplasms Measures Mediating Medical Methyl-CpG-Binding Protein 2 Modeling Molecular Mutation Myeloid Leukemia Myeloproliferative disease Normal Cell Nucleosomes Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Property Refractory Regulation Relapse Reporter Genes Research Personnel Signal Transduction System Testing The Sun Therapeutic Therapeutic Effect Toxic effect University of Texas M D Anderson Cancer Center Vorinostat Work arm base cancer cell cancer therapy cell growth clinical efficacy demethylation design drug development efficacy trial epigenome epigenomics genome wide association study genome-wide histone modification improved infancy inhibitor/antagonist leukemia meetings neoplastic novel novel strategies oncology programs randomized trial release of sequestered calcium ion into cytoplasm research study response response marker screening transcriptome sequencing

项目摘要

Three lines of evidence have converged to confirm the importance of epigenetic deregulation in leukemias: (i) The epigenome is markedly abnormal in leukemic cells; (ii) mutations in epigenetic regulators are very frequent in myeloid leukemias and (iii) drugs that modulate the epigenome (DNA methylation inhibitors, histone deacetylase inhibitors) are clinically effective in subsets of patients with myeloid leukemia. In the previous funding period, we developed a cellular screening system to identify drugs that reactivate the expression of an epigenetically silenced reporter gene. Using this model, we demonstrated that chromatin resetting and nucleosome depletion are key to reactivation of gene expression, and that demethylation is essential to ensure long term expression. We then screened a drug library of FDA approved compounds for single agent activity, as well as activity in combination with DNA methylation inhibitors. This screen identified dozens of drugs with epigenetic activity, including all three known epigenetic regulators in the library (decitabine, azacitidine, vorinostat). Some of the drugs identified have known anti-neoplastic properties (e.g. arsenic trioxide) but most did not, and instead were developed for other medical indications (e.g. cardiac drugs). Many of these drugs share the property of affecting calcium fluxes, and we traced their epigenetic effects to signaling through calmodulin kinase resulting in displacement of methyl-binding proteins. In the synergy screens, we found strong synergy between hypomethylators and DNA damaging agents such as carboplatin which we traced to disruption of binding by HP1, a chromatin regulator essential for gene silencing. Thus, we have identified new ways of reactivating gene expression that can be readily exploited therapeutically in clinical trials. These observations led to the hypotheses that drugs that work through therapeutic displacement of methyl-binding proteins and HP1 can augment epigenetic reprogramming of leukemic cells, and that these will increase the molecular and clinical efficacy of known epigenetic drugs. To test these hypotheses, we propose three specific aims: (1) Mechanism of action and therapeutic potential of drugs that reactivate gene expression through calcium signaling. (2) Mechanism of action and therapeutic potential of drugs that synergize with hypomethylating agents in activation of gene expression. (3) Clinical trials of novel, mechanism based DAC combinations in relapsed/refractory AML and MDS. This grant proposal aims at improving the efficacy of epigenetic therapy in myeloid leukemias, an approach that has already contributing to prolonging sun/ival in these diseases. RELEVANCE (See instructions): This project aims at developing new strategies for epigenetic therapy - a form of anti-cancer therapy that relies on reprogramming the epigenome or reeducation of the cancer cells to become closer to normal cells. The strategy has been successful in the past, and the new treatments approaches developed have the potential to increase cure rates in myeloid leukemias and could also find wide application in oncology.

三种证据已融合，以确认表观遗传放松在白血病中的重要性：（i）白血病细胞中的表观基因组明显异常；（ii）表观遗传调节剂的突变非常经常在调节表观基因组的髓样白血病和（III）药物（DNA甲基化抑制剂，组蛋白脱乙酰基酶抑制剂）在髓样白血病患者的亚群中具有临床有效。在以前的资金期，我们开发了一个细胞筛查系统，以鉴定重新激活的药物表观遗传沉默的记者基因的表达。使用此模型，我们证明了染色质重置和核小体耗竭是基因表达重新激活的关键，而脱甲基是确保长期表达的必不可少。然后，我们筛选了FDA批准化合物的药物库单药活性以及与DNA甲基化抑制剂结合的活性。此屏幕确定数十种具有表观遗传活性的药物，包括图书馆中所有三个已知的表观遗传调节剂（Decitabine，Azacitidine，Vorinostat）。确定的一些药物具有已知的抗塑性特性（例如砷三氧化物），但大多数没有，而是为其他医学迹象而开发的（例如心脏药物）。这些药物中有许多具有影响钙通量的特性，我们追踪了它们的表观遗传学通过钙调蛋白激酶对信号的影响，导致甲基结合蛋白的位移。在协同屏幕，我们发现低甲基甲基和DNA损伤药物（例如我们追溯到Carboplatin the hp1的结合破坏了，这是基因必不可少的染色质调节剂沉默。因此，我们已经确定了重新激活基因表达的新方法，可以很容易利用在临床试验中进行治疗。这些观察结果导致了通过起作用的药物的假设甲基结合蛋白和HP1的治疗位移可以增强表观遗传重编程白血病细胞，这些将增加已知表观遗传药物的分子和临床功效。到检验这些假设，我们提出了三个具体目的：（1）作用机理和治疗潜力机理通过钙信号传导重新激活基因表达的药物。（2）作用机理和治疗机理与低甲基化剂在基因表达激活中协同作用的药物的潜力。（3）临床基于机理的新型DAC组合的试验，复发/难治性AML和MDS。这笔赠款提案旨在提高表观遗传疗法在髓样白血病中的功效，这种方法具有这些疾病中已经有助于延长延长太阳/ival。相关性（请参阅说明）：该项目旨在制定表观遗传疗法的新策略 - 一种抗癌疗法的形式依赖于重编程表观基因组或癌细胞的再教育，以使其接近正常细胞。过去的策略已经成功了，而开发的新疗法方法具有增加髓样白血病的治愈率的潜力，也可能在肿瘤学中找到广泛的应用。