Targeting the aberrant kinome-epigenome in AML

靶向 AML 中的异常激酶组-表观基因组

基本信息

批准号：
8828591
负责人：
Ramiro Garzon
金额：
$ 30.77万
依托单位：
OHIO STATE UNIVERSITY
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：
2012-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8828591
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 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 Schedule Signal Transduction Stat5 protein Testing Transcription Repressor/Corepressor Tumor Suppressor Genes Tyrosine Kinase Inhibitor bone marrow hyperplasia clinical efficacy epigenome improved in vivo inhibitor/antagonist leukemia leukemia treatment leukemogenesis novel novel strategies novel therapeutic intervention novel therapeutics older patient outcome forecast overexpression pharmacodynamic model pre-clinical preclinical study promoter response structural genomics therapeutic target

项目摘要

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.

描述（由申请人提供）：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靶向酪氨酸激酶受体（TKR）基因的突变是骨髓性白血病发生的关键因素，尽管新的化合物具有激酶组（TKR抑制剂）的异常特征。）和表观基因组（DNMT 抑制剂）在 AML 中的应用已在临床试验中进行了测试，对它们作为单一药物的反应已经短期的，表明单一机制可能不足以克服 AML，我们推断，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。为了开发这种方法，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 TKR（KIT 和 FLT3）的表达，对于 AML 中表观基因组（DNA 甲基化）和激酶组的调节至关重要。此外，我们发现，高水平的 miR-29b 可以预测老年 AML 患者对低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/ 可以在药理学上增加内源性 miR-29b。因此，我们在这里截取了NFkB干扰化合物（硼替佐米）和组蛋白脱乙酰酶抑制剂的先发性药理学增加，否则较低。 miR-29b 细胞的内源水平将增强地西他滨的抗白血病活性，并在老年 AML 患者中产生更持久的临床反应。我们建议通过以下具体目标实施这一策略：具体目标 1：进行 1 期临床。在老年（≥60）AML患者中进行硼替佐米和索拉非尼联合治疗，然后使用地西他滨的试验，以确定：（a）硼替佐米/索拉非尼组合；(b) II 期推荐剂量和 (c) 与 miR-29b 靶向活性相关的药效 (PD) 终点：使用硼替佐米和索拉非尼进行 2 期临床试验。在新诊断的老年（≥60）AML患者中使用地西他滨，以便：（a）评估该组合的临床疗效；（b）验证该组合活性的生物学机制通过将生物学终点（例如，miR-29b）与临床反应相关联。具体目标#3：研究 HDAC 抑制剂（即 AR42）是否也会破坏 HDAC/Sp1-NF:B 复合物，从而增强 miR-29b 表达。当在临床前环境中与硼替佐米和索拉非尼联合使用时，我们将进一步提高对地西他滨的反应率。体内研究，以便：(a) 通过进行 PK/PD 建模确定导致 miR-29b 最高表达的 AR42 最佳剂量；(b) 评估 AR42/硼替佐米/索拉非尼组合随后与地西他滨的存活率进行比较单独使用硼替佐米/索拉非尼或 AR42，然后使用地西他滨； (c) 推荐最佳剂量/时间表； AR42/硼替佐米/索拉非尼，然后是地西他滨，用于人体 I 期试验。