Epigenetics and Epigenetic Therapy in AML

AML 的表观遗传学和表观遗传学治疗

• 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
• 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

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.

有三条证据表明表观遗传失调在白血病中的重要性： (i)表观基因组在白血病细胞中明显异常;（ii）表观遗传调节因子的突变非常 在骨髓性白血病中常见，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）在患有髓性白血病的患者亚群中是临床有效的。在 在上一个资助期，我们开发了一种细胞筛选系统，以识别重新激活 表观遗传学沉默的报告基因的表达。使用这个模型，我们证明了染色质 重置和核小体消耗是基因表达重新激活的关键，去甲基化是 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， 单一药剂活性以及与DNA甲基化抑制剂组合的活性。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，而是开发用于其他医学适应症（如心脏 药物）。这些药物中的许多都具有影响钙流的特性，我们追踪了它们的表观遗传 对通过钙调蛋白激酶的信号传导的影响，导致甲基结合蛋白的置换。在 协同筛选，我们发现低甲基化剂和DNA损伤剂之间有很强的协同作用， 卡铂，我们追踪到HP 1的结合破坏，HP 1是基因表达所必需的染色质调节因子， 沉默因此，我们已经确定了重新激活基因表达的新方法， 临床试验中的治疗效果。这些观察导致了一种假设，即药物通过 甲基结合蛋白和HP 1的治疗性置换可以增强表观遗传重编程， 白血病细胞，并且这些将增加已知表观遗传药物的分子和临床功效。到 为了验证这些假设，我们提出了三个具体目标：（1）作用机制和治疗潜力 通过钙信号重新激活基因表达的药物。(2)作用机制和治疗 与低甲基化剂协同作用以激活基因表达的药物的潜力。(3)临床 在复发性/难治性AML和MDS中进行的基于机制的新型DAC组合的试验。这笔赠款 一项提案旨在提高骨髓性白血病表观遗传治疗的疗效， 已经导致了这些疾病的日照时间延长。 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编程或对癌细胞进行再教育，使其更接近正常细胞。 该策略在过去是成功的，开发的新治疗方法具有 有可能提高髓性白血病的治愈率，也可能在肿瘤学中得到广泛应用。