Therapeutic Elimination of Stem Cells for Relapsed Pediatric AML

治疗性清除干细胞治疗复发性儿童 AML

• 批准号: 9038334
• 负责人: Yang Liu
• 金额: $ 47.21万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-11 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038334
• 关键词: Acute Myelocytic Leukemia; Address; Adult; Award; Biological Assay; Child; Childhood Acute Myeloid Leukemia; Clinical; Clinical Trials; Colony-Forming Units Assay; Data; Disease remission; Dose; Drug Kinetics; Drug effect disorder; Echinomycin; Flow Cytometry; Foundations; Future; Gene Targeting; Genomics; Goals; Health; Hematologic Neoplasms; Human; Hypoxia Inducible Factor; In complete remission; Maintenance; Medical; Medical center; Methods; Modeling; Mus; Mutation; National Cancer Institute; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacy facility; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phase III Clinical Trials; Plant Roots; Plasma; Preparation; Relapse; Reporting; Research Personnel; Resistance; Solid Neoplasm; Stem cells; Symptoms; Testing; Therapeutic; Toxic effect; United States National Institutes of Health; assay development; base; cancer stem cell; chemotherapy; chromatin immunoprecipitation; effective therapy; human data; hypoxia inducible factor 1; inhibitor/antagonist; leukemia; leukemic stem cell; mouse model; next generation sequencing; nonhuman primate; novel strategies; phase 1 study

DESCRIPTION (provided by applicant): Current therapy can result in complete remission (CR) in nearly 90% of pediatric acute myeloid leukemia (AML) patients. Unfortunately, relapse AML (rAML) occurs in almost 50% of patients within two years of CR. Among them, more than 60% succumbed to AML within two years of relapse. Novel approaches are therefore needed to address the unmet medical needs of rAML. Recent studies suggest that leukemia stem cells (LSC) are highly resistant to conventional chemotherapy and thus are likely responsible for relapse. Therefore, therapeutic elimination of LSC may offer new approaches for the treatment of rAML. We have recently reported that hypoxia-inducible factor (HIF) 1a is activated in, and essential for, maintenance of AML stem cells. More importantly, at doses that have no recorded toxicity, Echinomycin, an HIF inhibitor, is effective in eliminating AML stem cells in xenogeneic mouse models and provides effective therapy for mouse rAML caused by mutations frequently found in pediatric AML. Echinomycin has been used in multiple phase I and phase II clinical trials in adult patients with solid tumors, although the drug has not been tested in hematological malignancies. Moreover, due to lack of analytic methods, these trials were performed without pharmacokinetic (PK) information. Nevertheless, these clinical trials demonstrated that Echinomycin is tolerated at doses that are 30- to 50-fold higher than our projected therapeutic doses based on data from xenogenic rAML models. Based on these exciting results, we propose herein a collaborative project involving investigators at Children's National Medical Center and the National Cancer Institute to carry out phase I clinical trials for children with relapsed AML. We will test the PK in non-human primates and fine-tune starting dose for human trials. We will also conduct dose escalation studies to identify a tolerable dose that results in significant reduction of rAML stem cells. We will develop and standardize a plasma inhibition assay for drug dosing in the future phase II and phase III clinical trials. Finally, to understand he mechanism of drug action, we will use chromatin- immunoprecipitation followed by next generation sequencing to identify HIF targets associated with the reduction of rAML stem cell activity. Our proposed studies will provide the much needed first-in-human data on PK/PD of Echinomycin, and provide a foundation for future phase II and phase III clinical trials aimed at the therapeutic elimination of cancer stem cells for pediatric AML.

描述（由申请人提供）：目前的治疗可以导致近90%的儿童急性髓性白血病（AML）患者完全缓解（CR）。不幸的是，近50%的患者在CR后两年内发生复发性AML（rAML）。其中，超过60%的人在复发后两年内死于AML。因此，需要新的方法来解决rAML未满足的医疗需求。最近的研究表明，白血病干细胞（LSC）对常规化疗具有高度耐药性，因此可能是复发的原因。因此，治疗性消除LSC可能为治疗rAML提供新的方法。我们最近报道了低氧诱导因子（HIF）1a在AML干细胞中被激活，并且对于维持AML干细胞至关重要。更重要的是，在没有记录毒性的剂量下，HIF抑制剂棘霉素可有效消除异种小鼠模型中的AML干细胞，并为儿科AML中常见的突变引起的小鼠rAML提供有效治疗。棘霉素已用于成人实体瘤患者的多个I期和II期临床试验，尽管该药物尚未在血液恶性肿瘤中进行测试。此外，由于缺乏分析方法，这些试验在没有药代动力学（PK）信息的情况下进行。然而，这些临床试验表明，棘霉素的耐受剂量比我们基于异种rAML模型数据预测的治疗剂量高30- 50倍。基于这些令人兴奋的结果，我们在此提出了一个合作项目，涉及儿童国家医学中心和国家癌症研究所的研究人员，对复发性AML儿童进行I期临床试验。我们将在非人类灵长类动物中测试PK，并微调人体试验的起始剂量。我们还将进行剂量递增研究，以确定导致rAML干细胞显著减少的耐受剂量。我们将在未来的II期和III期临床试验中开发和标准化用于药物给药的血浆抑制试验。最后，为了了解药物作用机制，我们将使用染色质免疫沉淀，然后进行下一代测序，以鉴定与rAML干细胞活性降低相关的HIF靶点。我们提出的研究将提供急需的关于棘霉素PK/PD的首次人体数据，并为未来旨在治疗性消除儿童AML的癌症干细胞的II期和III期临床试验提供基础。