Therapeutic Elimination of Stem Cells for Relapsed Pediatric AML

描述（由申请人提供）：目前的治疗可以使近90%的儿童急性髓性白血病（AML）患者完全缓解（CR）。不幸的是，几乎50%的患者在CR的两年内发生AML复发（rAML），其中60%以上的患者在两年内复发为AML。因此，需要新的方法来解决rAML未得到满足的医疗需求。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，因此可能导致复发。因此，治疗性消除LSC可能为rAML的治疗提供新的途径。我们最近报道了缺氧诱导因子（HIF） 1a在AML干细胞的维持中被激活，并且对其至关重要。更重要的是，在没有毒性记录的剂量下，Echinomycin（一种HIF抑制剂）在异种小鼠模型中有效地消除AML干细胞，并为儿童AML中常见的突变引起的小鼠rAML提供有效治疗。尽管尚未在血液系统恶性肿瘤中进行试验，但紫霉素已用于成人实体瘤患者的多个I期和II期临床试验。此外，由于缺乏分析方法，这些试验在进行时没有药代动力学（PK）信息。然而，这些临床试验表明，根据我们基于异种rAML模型的数据预测的治疗剂量，Echinomycin的耐受性剂量高出30- 50倍。基于这些令人兴奋的结果，我们在此提出一个合作项目，由国家儿童医学中心和国家癌症研究所的研究人员参与，对复发性急性髓性白血病儿童进行I期临床试验。我们将在非人类灵长类动物身上测试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，以确定可显著减少rAML干细胞的耐受剂量。我们将在未来的II期和III期临床试验中开发和规范血浆抑制测定药物剂量。最后，为了了解药物作用的机制，我们将使用染色质免疫沉淀和下一代测序来确定与rAML干细胞活性降低相关的HIF靶点。我们提出的研究将提供迫切需要的关于紫霉素的PK/PD的首次人体数据，并为未来针对儿童AML治疗性消除癌症干细胞的II期和III期临床试验提供基础。

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.