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:
- 金额:$ 30.77万
- 依托单位:
- 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:
- 关键词:AchievementAcute Myelocytic LeukemiaAssesAttentionBAY 54-9085Blast CellBloodBone MarrowBortezomibCellsChemotherapy-Oncologic ProcedureClinicClinicalClinical TrialsComplexDNADNA MethylationDNA Methyltransferase InhibitorDNA Modification MethylasesDNA methyltransferase inhibitionDecitabineDevelopmentDiseaseDisease remissionDoseDown-RegulationDrug KineticsESR1 geneElderlyEpigenetic ProcessFLT3 geneGene SilencingGenesGeneticGoalsHematopoieticHistone Deacetylase InhibitorHistonesHumanHypermethylationIn complete remissionLeadLifeMethylationModelingMolecular TargetMusMutateMutationMyelogenousNewly DiagnosedOutcomePatientsPharmaceutical PreparationsPharmacodynamicsPhasePhase I Clinical TrialsPhase II Clinical TrialsPhosphotransferasesProteasome InhibitorProteinsReceptor Protein-Tyrosine KinasesRecommendationRecruitment ActivityRegulationReportingScheduleSignal TransductionStat5 proteinTestingTranscription Repressor/CorepressorTumor Suppressor GenesTyrosine Kinase Inhibitorbone marrow hyperplasiaclinical efficacyepigenomeimprovedin vivoinhibitor/antagonistleukemialeukemia treatmentleukemogenesisnovelnovel strategiesnovel therapeutic interventionnovel therapeuticsolder patientoutcome forecastoverexpressionpharmacodynamic modelpre-clinicalpreclinical studypromoterresponsestructural genomicstherapeutic 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):造血分化相关基因的表观遗传沉默和编码造血细胞增殖相关酪氨酸激酶受体(TKR)的基因突变是髓系白血病发生的关键因素。尽管靶向AML中激酶组(TKR抑制剂)和表观基因组(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,但作为单一药物对它们的反应是短暂的,这表明单一机制可能不足以克服AML。我们推断,与单靶点方法相比,同时分子靶向可能导致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,我们已经表明,miR-29 b是通过靶向和抑制TKR(KIT和FLT 3)和DNMT的表达来调节AML中表观基因组(DNA甲基化)和激酶组的核心。此外,我们发现高水平的miR-29 b可预测老年AML患者对低甲基化剂地西他滨的敏感性。在临床前研究中,我们发现TKI(索拉非尼),Sp1/NFkB干扰化合物(硼替佐米)和组蛋白去乙酰化酶抑制剂可显著增加内源性miR-29 b。因此,我们在此假设,预先药理学增加原本较低的内源性miR-29 b细胞水平将增强地西他滨的抗白血病活性,并导致老年AML患者更持久的临床应答。我们建议通过以下具体目标来实施这一策略:具体目标#1:在老年(≥60岁)AML患者中进行一项1期临床试验,先使用硼替佐米和索拉非尼联合治疗,然后使用地西他滨,以确定:(a)生物学有效剂量和耐受剂量(BETD)硼替佐米/索拉非尼联合治疗;(B)II期推荐剂量和(c)与miR-29 B的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(≥60岁)AML患者中进行硼替佐米和索拉非尼B随后地西他滨的II期临床试验,以:(a)评估联合用药的临床疗效;(B)通过将生物学终点(例如,miR-29 B)与临床应答相关联来验证联合用药活性的生物学机制。具体目标#3:研究HDAC抑制剂(即,AR 42),其也破坏HDAC/Sp1-NF:B复合物,当在临床前环境中与硼替佐米和索拉非尼B组合时增强miR-29 B表达,进而进一步改善对地西他滨的响应率。我们将进行临床前体内研究,以便:(a)通过进行PK/PD建模来确定导致miR-29 B最高表达的AR 42的最佳剂量;(B)评估与单独的硼替佐米/索拉非尼B或单独的AR 42接着地西他滨相比,组合AR 42/硼替佐米/索拉非尼B接着地西他滨的存活;(c)推荐AR 42/硼替佐米/索拉非尼随后地西他滨的最佳剂量/时间表,用于在人类I期环境中进行测试。
项目成果
期刊论文数量(0)
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Ramiro Garzon其他文献
Ramiro Garzon的其他文献
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{{ truncateString('Ramiro Garzon', 18)}}的其他基金
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AML 中非编码 RNA 的生物学和靶向
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Biology and Targeting of noncoding RNAs in AML
AML 中非编码 RNA 的生物学和靶向
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Training Hematology and Oncology Fellows in Clinical Research
培训血液学和肿瘤学研究员进行临床研究
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10188469 - 财政年份:2020
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$ 30.77万 - 项目类别:
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 - 财政年份:2012
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$ 30.77万 - 项目类别:
Targeting the aberrant kinome-epigenome in AML
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8634056 - 财政年份:2012
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$ 30.77万 - 项目类别:
Targeting the aberrant kinome-epigenome in AML
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$ 30.77万 - 项目类别:
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 - 财政年份:2012
- 资助金额:
$ 30.77万 - 项目类别:
Role of the ultraconserved genomic regions (UCRs) in hematopoiesis
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- 批准号:
7978154 - 财政年份:2010
- 资助金额:
$ 30.77万 - 项目类别:
Role of the ultraconserved genomic regions (UCRs) in hematopoiesis
超保守基因组区域 (UCR) 在造血中的作用
- 批准号:
8119543 - 财政年份:2010
- 资助金额:
$ 30.77万 - 项目类别:
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