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.

三种证据共同证实了表观遗传失调在白血病中的重要性： (i) 白血病细胞的表观基因组明显异常； (ii) 表观遗传调节因子的突变非常严重常见于髓性白血病和 (iii) 调节表观基因组的药物（DNA 甲基化抑制剂、组蛋白脱乙酰酶抑制剂）对部分髓系白血病患者具有临床效果。在在之前的资助期间，我们开发了一种细胞筛选系统来识别重新激活细胞的药物表观遗传沉默报告基因的表达。使用这个模型，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，而去甲基化是对于确保长期表达至关重要。然后我们筛选了 FDA 批准的化合物的药物库单一药物活性，以及与 DNA 甲基化抑制剂联合使用的活性。该屏幕识别出数十种具有表观遗传活性的药物，包括库中所有三种已知的表观遗传调节剂（地西他滨、阿扎胞苷、伏立诺他）。一些已确定的药物具有已知的抗肿瘤特性（例如三氧化二砷），但大多数没有，而是为其他医学适应症（例如心脏病）而开发药物）。许多这些药物都具有影响钙通量的特性，我们追踪了它们的表观遗传对钙调蛋白激酶信号传导的影响，导致甲基结合蛋白的置换。在协同作用筛选，我们发现低甲基化剂和 DNA 损伤剂之间有很强的协同作用，例如我们追踪到卡铂与 HP1 的结合受到破坏，HP1 是基因必需的染色质调节因子沉默。因此，我们已经确定了可以轻松利用的重新激活基因表达的新方法在临床试验中具有治疗作用。这些观察结果导致了这样的假设：药物可以通过甲基结合蛋白和 HP1 的治疗性置换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疗效。到为了检验这些假设，我们提出了三个具体目标：（1）作用机制和治疗潜力通过钙信号传导重新激活基因表达的药物。（二）作用机制及治疗作用与低甲基化药物协同激活基因表达的潜力。 (三)临床基于新机制的 DAC 组合治疗复发/难治性 AML 和 MDS 的试验。这笔补助金该提案旨在提高表观遗传疗法治疗髓系白血病的疗效，这种方法已已经有助于延长这些疾病的日照/伊瓦尔时间。相关性（参见说明）：该项目旨在开发表观遗传疗法的新策略——一种抗癌疗法，依赖于对表观基因组进行重新编程或对癌细胞进行重新教育，使其更接近正常细胞。该策略过去曾取得成功，并且开发的新治疗方法具有具有提高髓系白血病治愈率的潜力，并且还可以在肿瘤学中得到广泛应用。