Targeting the aberrant kinome-epigenome in AML

靶向 AML 中的异常激酶组-表观基因组

• 批准号: 8239385
• 负责人: Ramiro Garzon
• 金额: $ 31.04万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239385
• 关键词: Achievement; Acute Myelocytic Leukemia; Asses; Attention; BAY 54-9085; Blast Cell; Blood; Bone Marrow; Bortezomib; Cells; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Clinical Trials; Complex; DNA; DNA Methylation; DNA Methyltransferase; DNA Methyltransferase Inhibitor; DNA Modification Methylases; DNA methyltransferase inhibition; Decitabine; Development; Disease; Disease remission; Dose; Down-Regulation; Drug Kinetics; ESR1 gene; Elderly; Epigenetic Process; FLT3 gene; Gene Silencing; Genes; Genetic; Goals; Hematopoietic; Histone Deacetylase Inhibitor; Histones; Human; Hypermethylation; In complete remission; Lead; Life; Methylation; Modeling; Molecular Target; Mus; Mutate; Mutation; Myelogenous; Newly Diagnosed; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phosphotransferases; Proteasome Inhibitor; Proteins; Receptor Protein-Tyrosine Kinases; Recommendation; Recruitment Activity; Regulation; Reporting; STAT5A gene; Schedule; Signal Transduction; Testing; Transcription Repressor/Corepressor; Tumor Suppressor Genes; Tyrosine Kinase Inhibitor; bone marrow hyperplasia; clinical efficacy; improved; in vivo; inhibitor/antagonist; leukemia; leukemogenesis; novel; novel strategies; novel therapeutic intervention; novel therapeutics; outcome forecast; overexpression; pharmacodynamic model; pre-clinical; preclinical study; promoter; response; structural genomics; therapeutic target

DESCRIPTION (provided by applicant): Epigenetic silencing of genes involved in hematopoietic differentiation and mutations in genes encoding tyrosine kinase receptors (TKRs) involved in hematopoietic cell proliferation are critical players in myeloid leukemogenesis. Although novel compounds targeting the aberrant features of kinome (TKR inhibitors) and epigenome (DNMT inhibitors) in AML have been tested in clinical trials, the response to them as single agents has been short-lived, suggesting that a single mechanism may not be sufficient to overcome AML. We reasoned that concurrent molecular targeting may result in better antileukemic activity compared with single target approaches. In order to develop such approach, the mechanism of leukemogenesis needs to be understood. Recently, we have shown that miR-29b is central to regulation of both epigenome (DNA methylation) and kinome in AML by targeting and repressing the expression of TKRs (KIT and FLT3) and DNMTs. Furthermore, we showed that high levels of miR-29b are predictive of sensitivity to the hypomethylating agent decitabine in older AML patients. In preclinical studies, we showed that endogenous miR-29b can be pharmacologically increased with TKI (sorafenib), Sp1/NFkB interfering compounds (bortezomib) and histone deacetylase inhibitors. Therefore, we hypothesize here that a pre-emptive pharmacologic increase of otherwise low endogenous levels of miR-29b cells will enhance the antileukemia activity of decitabine and lead to a more durable clinical response in older AML patients. We propose to pursue this strategy through the following specific aims: Specific Aim #1: To conduct a Phase 1 clinical trial with bortezomib and sorafenib in combination followed by decitabine in elderly (>60) AML patients in order to determine: (a) the biologically effective and tolerable dose (BETD) of bortezomib/sorafenib combination; (b) a phase II recommended dose and (c) pharmacodynamic (PD) endpoints related to the targeting activity of miR-29b. Specific Aim #2: To conduct a Phase 2 clinical trial with bortezomib and sorafenib followed by decitabine in newly diagnosed elderly (>60) AML patients in order to: (a) assess clinical efficacy of the combination;(b) to validate the biologic mechanisms of activity of the combination by correlating biologic endpoints (e.g,miR-29b,) with clinical response. Specific Aim #3: To investigate whether HDAC inhibitors (i.e., AR42), which also disrupts the HDAC/Sp1-NF:B complex, enhance miR-29b expression when combined with bortezomib and sorafenib in the preclinical setting and in turn improve even further the response rate to decitabine. We will conduct preclinical in vivo studies in order to: (a) determine the optimal dose of AR42 that leads to the highest expression of miR-29b by performing PK/PD modeling; (b) asses survival of the combination AR42/bortezomib/sorafenib followed by decitabine as compared with bortezomib/sorafenib or AR42 alone followed by decitabine; (c) recommendation of an optimal dose/schedule of the AR42/bortezomib/sorafenib followed by decitabine for testing in the phase I setting in humans. PUBLIC HEALTH RELEVANCE: Over the past 20 years there has been little improvement in AML treatments, especially for elderly (>60) patients with only a few of them survival for more than 2 years. Lack of significant improvement in the current results calls attention to the need for development of novel therapeutic strategies. The overall goal of this proposal is to test in the clinic a novel approach to target leukemia mechanisms with drugs (bortezomib and sorafenib) that have been already approved for use in mankind, but combined in a new manner that will allow increase of a molecules (miR-29b) that can control these leukemia mechanisms and may improve the clinical response and outcome of AML patients treated with decitabine, an agent that by itself already has shown encouraging results.

描述(申请人提供)：参与造血分化的基因的表观遗传沉默和参与造血细胞增殖的编码酪氨酸激酶受体(TKRs)的基因突变是髓系白血病发生的关键因素。尽管针对急性髓系白血病中的激动组(TKR抑制剂)和表观基因组(DNMT抑制剂)的异常特征的新化合物已经在临床试验中被测试，但作为单一药物对它们的反应是短暂的，这表明单一的机制可能不足以克服AML。我们推测，与单一靶点方法相比，并行分子靶向可能会产生更好的抗白血病活性。为了发展这种方法，需要了解白血病发生的机制。最近，我们发现miR-29b通过靶向和抑制TKRs(Kit和Flt3)和Dnmts的表达，在AML的表观基因组(DNA甲基化)和动态组的调控中发挥核心作用。此外，我们还发现，在老年AML患者中，miR-29b的高水平预示着对去甲基化药物地西他滨的敏感性。在临床前研究中，我们发现TKI(索拉非尼)、Sp1/NFkB干扰化合物(Bortezomib)和组蛋白脱乙酰酶抑制剂可以从药理上增加内源性miR-29b。因此，我们在这里假设，先发制人地增加内源性低水平的miR-29b细胞将增强地西他滨的抗白血病活性，并在老年AML患者中导致更持久的临床反应。我们建议通过以下具体目标来推行这一战略：具体目标1：在老年(&gt；60)AML患者中联合使用bortezomib和sorafenib，然后使用地西他滨进行一期临床试验，以确定：(A)bortezomib/sorafenib组合的生物有效和耐受量(BETD)；(B)第二阶段推荐剂量；(C)与miR-29b靶向活性相关的药效学(PD)终点。具体目标#2：在新诊断的老年(&gt；60)AML患者中进行波特佐米、索拉非尼和地西他滨的第二阶段临床试验，以：(A)评估联合用药的临床疗效；(B)通过将生物终点(例如miR-29b)与临床反应相关联来验证联合用药的生物学作用机制。具体目标#3：研究HDAC抑制剂(即AR42)，也破坏HDAC/Sp1-NF：B复合体，在临床前环境下与Bortezomib和Sorafenib联合使用是否能增强miR-29b的表达，进而进一步提高对地西他滨的应答率。我们将开展临床前体内研究，以：(A)通过进行PK/PD建模，确定导致miR-29b基因表达最高的AR42的最佳剂量；(B)评估AR42/bortezomib/sorafenib联合用药与Bortezomib/sorafenib或AR42单独用药后用地西他滨的比较；(C)建议AR42/bortezomib/sorafenib先用药后再用地西他滨进行I期临床试验的最佳剂量/时间表。 与公共卫生相关：在过去的20年里，急性髓细胞白血病的治疗几乎没有改善，特别是对只有少数存活超过两年的老年患者(&gt；60)。目前的结果缺乏显着的改善，这就要求人们注意开发新的治疗策略的必要性。这项建议的总体目标是在临床上测试一种新的方法，以靶向白血病机制的药物(bortezomib和sorafenib)，这些药物已经被批准用于人类，但以一种新的方式结合起来，将允许增加可以控制这些白血病机制的分子(miR-29b)，并可能改善使用地西他滨治疗的AML患者的临床反应和结果。地西他滨本身已经显示出令人鼓舞的结果。