Pharmacological modulation of epigenetic changes in AML

AML 表观遗传变化的药理学调节

• 批准号: 8826033
• 负责人: Monica L Guzman
• 金额: $ 35.96万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826033
• 关键词: Aberrant DNA Methylation; Acute Myelocytic Leukemia; Adult; Adult Acute Myeloblastic Leukemia; Aftercare; Attention; Blast Cell; Bortezomib; Cancer and Leukemia Group B; Chemotherapy-Oncologic Procedure; Child; Childhood Acute Myeloid Leukemia; Clinic; Clinical; Clinical Trials; Complement; DNA; Data; Decitabine; Disease; Disease remission; Dose; Drug Kinetics; Elderly; Epigenetic Process; FDA approved; Failure; Funding; Gene Expression; Gene Silencing; Genes; Genetic; Goals; Grant; Health; Histone Deacetylase Inhibitor; Hypermethylation; Indium; Laboratory Study; Leadership; Mediating; Methylation; MicroRNAs; Molecular; Mutation; Myelogenous; Ohio; Outcome; Paper; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Phosphotransferases; Predictive Value; Process; Proteasome Inhibitor; Proteins; Publications; Publishing; Recruitment Activity; Refractory; Regimen; Relapse; Reporting; Research; Resistance; Role; Safety; Series; Testing; Therapeutic; Toxic effect; Translational Research; Universities; Up-Regulation; age group; arm; base; bone marrow hyperplasia; chemotherapy; clinical efficacy; clinical predictors; design; gene function; genome wide methylation; genome-wide; high risk; improved; insight; leukemic stem cell; leukemogenesis; member; molecular marker; novel; novel strategies; novel therapeutic intervention; pediatric patients; prognostic value; resistance mechanism; response; stem cell biology; success; targeted treatment; therapeutic target; tripolyphosphate; two-arm study; young adult

DESCRIPTION (provided by applicant): The majority of children and adults with acute myeloid leukemia (AML) die of their disease and therefore, novel therapeutic approaches beyond "one-fits-all" chemotherapy regimens are required. Epigenetic gene silencing has been reported to be involved in the deregulation of hematopoietic cell proliferation, differentiation and survival in AML and contributes to leukemogenesis. We have been focusing on pharmacological targeting of aberrant DNA methylation that mediates epigenetic gene silencing in AML. Decitabine (DAC) is an azanucleoside with hypomethylating activity. In the last funding cycle of this R01 grant, we have brought to the clinic and demonstrated the excellent activity of a regimen of low-dose DAC (20 mg/m2/day x10 day) and the feasibility of the combination of DAC with the proteasome inhibitor bortezomib. We have shown that untreated older AML patients can achieve a complete remission rate of approximately 50% with these DAC-based regimens. In addition we have made several discoveries with regard to: (a) potential molecular predictors of clinical response to DAC (miR-29b and DNMT3A mutations); (b) novel mechanisms of myeloid leukemogenesis involving epigenetics, microRNAs and kinases, and (c) novel compounds that enhance the pharmacologic activity of DAC through up regulation of microRNAs (i.e., AR42, a histone deacetylase inhibitor designed and developed at the OSU). These novel clinical, molecular and pharmacologic findings now need to be validated and their mechanisms further understood in order to move forth the epigenetic-targeting approaches in AML. To achieve this goal, we also need to define the molecular basis for treatment resistance to epigenetic-targeting therapies, not only at the level of bulk AML blasts, but also in leukemia stem cells (LSC). Thus, we have now designed two new clinical trials and a series of novel pharmacodynamic studies that will unveil the interplay among DNA hypermethylation, microRNAs, and LSC through the following Specific Aims: (1)To conduct a larger Phase II clinical trial (CALGB 11002) in untreated older (>60 years) AML to compare the clinical activity of decitabine (DAC) vs. decitabine (DAC) + bortezomib and identify the predictive and pharmacodynamic (PD) factors that determine therapeutic differences between these two regimens; (2) To conduct a Phase I clinical trial (OSU 11130) of the HDAC inhibitor AR42 followed by DAC (AR42->DAC) to define toxicity, clinical response and pharmacokinetic (PK) and pharmacodynamic (PD) factors that determine the clinical outcomes in adult and pediatric patients with AML; (3) To determine the impact of epigenetic- targeting therapies on the function and survival of leukemic stem cells (LSCs) and how this contributes to disease response or resistance in AML patients to DAC-based regimens.

描述（由申请人提供）：大多数患有急性髓性白血病（AML）的儿童和成人死于他们的疾病，因此需要新的治疗方法，而不是“一刀切”的化疗方案。据报道，表观遗传基因沉默参与AML中造血细胞增殖、分化和存活的失调，并有助于白血病的发生。我们一直专注于在AML中介导表观遗传基因沉默的异常DNA甲基化的药理学靶向。地西他滨（DAC）是一种具有低甲基化活性的氮杂核苷。在这项R01资助的最后一个资助周期中，我们已经将低剂量DAC （20mg /m2/day x10 day）方案带入临床并证明了其出色的活性，以及DAC与蛋白酶体抑制剂硼替佐米联合使用的可行性。我们已经证明，未经治疗的老年AML患者使用这些基于dac的方案可以达到约50%的完全缓解率。此外，我们还在以下方面取得了一些发现：(a) DAC临床反应的潜在分子预测因子（miR-29b和DNMT3A突变）；(b)涉及表观遗传学、microrna和激酶的髓系白血病发生的新机制，以及(c)通过上调microrna来增强DAC药理学活性的新化合物（即由俄勒冈州立大学设计和开发的组蛋白去乙酰化酶抑制剂AR42）。这些新的临床、分子和药理学发现现在需要得到验证，并进一步了解它们的机制，以便推进AML的表观遗传靶向治疗方法。为了实现这一目标，我们还需要确定表观遗传靶向治疗耐药的分子基础，不仅在AML原细胞水平，而且在白血病干细胞（LSC）水平。因此，我们现在设计了两项新的临床试验和一系列新的药效学研究，将通过以下具体目标揭示DNA超甲基化，microrna和LSC之间的相互作用：(1)在未治疗的老年（60岁以上）AML患者中开展更大规模的II期临床试验（CALGB 11002），比较地西他滨（DAC）与地西他滨(DAC) +硼替佐米的临床活性，并确定决定这两种方案治疗差异的预测和药效学（PD）因素；(2)开展HDAC抑制剂AR42和DAC （AR42->DAC）的I期临床试验（OSU 11130），以确定成人和儿童AML患者的毒性、临床反应和药代动力学（PK）和药效学（PD）因素，这些因素决定了临床结果；(3)确定表观遗传靶向治疗对白血病干细胞（LSCs）功能和存活的影响，以及这如何促进AML患者对基于dac的方案的疾病反应或耐药性。