Pharmacological modulation of epigenetic changes in AML

AML 表观遗传变化的药理学调节

• 批准号: 8505766
• 负责人: Monica L Guzman
• 金额: $ 32.29万
• 依托单位: OHIO STATE UNIVERSITY
• 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/8505766
• 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; 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; 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; 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; 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; prognostic; public health relevance; resistance mechanism; response; stem cell biology; success; 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）的儿童和成人死于其疾病，因此，需要超越“一刀切”化疗方案的新治疗方法。表观遗传基因沉默已被报道参与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。我们一直专注于药物靶向异常DNA甲基化介导的表观遗传基因沉默在AML。地西他滨（DAC）是具有低甲基化活性的氮杂核苷。在R 01资助的最后一个资助周期中，我们已经将低剂量DAC（20 mg/m2/天x10天）方案带到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组合的可行性。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，我们已经在以下方面取得了几项发现：（a）对DAC的临床反应的潜在分子预测因子（miR-29 B和DNMT 3A突变）;（B）涉及表观遗传学、microRNA和激酶的髓性白血病发生的新机制，以及（c）通过上调microRNA（即，AR 42，一种在OSU设计和开发的组蛋白脱乙酰酶抑制剂）。这些新的临床、分子和药理学发现现在需要得到验证，并进一步了解其机制，以推进急性髓细胞白血病的表观遗传靶向方法。为了实现这一目标，我们还需要确定对表观遗传靶向疗法的治疗耐药性的分子基础，不仅在大量AML原始细胞水平上，而且在白血病干细胞（LSC）中。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，这些研究将通过以下特定目的揭示DNA超甲基化，microRNA和LSC之间的相互作用：（1）开展更大规模的II期临床试验（CALGB 11002）在未经治疗的老年人中（>60岁）AML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预测和药效学（PD）决定这两种方案之间治疗差异的因素;（二）开展一期临床试验（OSU 11130）的HDAC抑制剂AR 42，随后是DAC（AR 42->DAC）来定义毒性，决定成人和儿童AML患者临床结局的临床应答以及药代动力学（PK）和药效学（PD）因素;（3）确定表观遗传靶向疗法对白血病干细胞（LSC）的功能和存活的影响，以及这如何有助于AML患者对基于DAC的方案的疾病应答或抗性。