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: 9055657
• 负责人: Ramiro Garzon
• 金额: $ 30.9万
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9055657
• 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; Molecular Target; 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; mouse model; 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

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（通过应用提供）：参与造血分化和突变的基因的表观遗传沉默，与造血细胞增殖相关的酪氨酸激酶受体（TKR）（TKR）是髓样白血病生成的关键参与者。尽管针对Kinome（TKR抑制剂）和AML中表观基因组（DNMT抑制剂）的异常特征的新型化合物已在临床试验中进行了测试，但作为单一试剂的反应已短暂，表明一种机制可能不足以胜过AML。我们认为，与单​​个靶方法相比，并发分子靶向可能会导致更好的抗死性活性。为了开发这种方法，需要了解白血病的机制。最近，我们表明miR-29b是通过靶向和抑制TKRS（KIT和FLT3）和DNMT的表达来调节AML中表观基因组（DNA甲基化）和Kinome的核心。此外，我们表明，高水平的miR-29b可以预测对年龄较大AML患者中甲基化剂决decideabine的敏感性。在临床前研究中，我们表明内源性miR-29b可以通过TKI（Sorafenib），SP1/NFKB干扰化合物（Bortezomib）和组蛋白脱乙酰基酶抑制剂来增加药物。因此，我们在这里假设，否则低内源水平的miR-29b细胞的先发性药物增加将增强decideabine的抗肺炎活性，并导致老年AML患者的临床反应更加持久。我们建议通过以下特定目的来实现这一策略：具体目的＃1：与Bortezomib和Sorafenib组合进行1阶段临床试验，然后在古老的AML患者（≥60）AML患者中进行Decideeabine，以确定：（a）生物学上有效和可耐受性剂量（Betd）的bortezomib/sorafeafenib borteafezomib sorafenib组合； （b）II期推荐剂量和（c）与miR-29b靶向活性有关的药效（PD）终点。具体目的＃2：用硼替唑和索拉非尼进行2期临床试验，然后在新诊断的AML患者（≥60）患者中进行Decideabine进行：（a）评估组合的临床效率； （b）通过将生物学终点（例如miR-29b，）与临床反应相关联，验证组合活性的生物学机制。特定目的＃3：要研究HDAC抑制剂（即AR42）是否会破坏HDAC/SP1-NF：B复合物，在与the前来环境中的硼替佐米和索拉非尼相结合时，增强了miR-29b的表达，进一步提高了响应率。我们将进行临床前研究研究，以：（a）确定通过执行PK/PD建模导致miR-29b表达最高表达的AR42的最佳剂量； （b）与硼替佐米/索拉非尼或AR42相比，AR42/Bortezomib/sorafenib组合的驴生存期，然后是Decideabine，然后是Decideabine； （c）建议AR42/Bortezomib/sorafenib的最佳剂量/时间表，然后是Decideabine进行人类I期设置进行测试。