Developing CRM1 inhibitors in AML

开发 AML 中的 CRM1 抑制剂

• 批准号: 9071394
• 负责人: Ramiro Garzon
• 金额: $ 31.96万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-16 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9071394
• 关键词: Active Biological Transport; Acute Myelocytic Leukemia; Apoptosis; Asses; Attention; Binding; Bioavailable; Biological Markers; Blast Cell; Cell Cycle Arrest; Cell Death; Cell Line; Cell Nucleus; Cells; Chromosomes; Clinic; Clinical; Collaborations; Complex; Correlative Study; Cytarabine; DNA; DNA Methylation; DNA topoisomerase II alpha; Data; Decitabine; Development; Disease; Dose; Down-Regulation; Drug Kinetics; Elderly; Enzymes; Epigenetic Process; FLT3 gene; Generations; Genes; Genetic; Genetic Transcription; Goals; Health; Hematopoietic; Human; Idarubicin; In Vitro; In complete remission; Literature; Maintenance; Malignant Neoplasms; Mediating; MicroRNAs; Molecular Cytogenetics; Mus; Myelogenous; Newly Diagnosed; Nuclear; Nuclear Export; Oncogenes; Oral; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Proteins; Refractory; Refractory Disease; Regimen; Relapse; Reporting; Resistance; Safety; Schedule; Sequential Treatment; Specimen; TP53 gene; Testing; Topoisomerase II; Topoisomerase-II Inhibitor; Treatment Protocols; Tumor Suppressor Proteins; Up-Regulation; base; cancer cell; chemotherapy; exportin 1 protein; improved outcome; in vivo; inhibitor/antagonist; leukemia; leukemia treatment; methylome; next generation sequencing; novel strategies; novel therapeutic intervention; novel therapeutics; outcome forecast; overexpression; phase 1 study; phase II trial; promoter; receptor; response; trafficking; transcriptome; treatment response

DESCRIPTION (provided by applicant): The prognosis of acute myeloid leukemia (AML) is poor, highlighting the urgent need for novel therapeutic approaches. CRM1 is a nuclear export receptor involved in the active transport of tumor suppressors (TS) [e.g. p53] out of the nucleus resulting in their inactivation. Over-expression of CRM1 protein has been described in AML. Targeting CRM1 using oral selective inhibitors resulted in significant nuclear accumulation of p53 and in turn high degree of apoptosis, cell-cycle arrest and myeloid differentiation in AML cell lines and patient blasts. Based on these preliminary data we hypothesize that CRM1 inhibitors will be safe and tolerated and will show single agent anti-leukemic activity in AML patients. A Phase 1 study of KPT-330 (last generation oral CRM1 inhibitors) in refractory/relapsed and newly diagnosed unfit elderly (>65 years) AML was started with the goal to assess safety, tolerability and preliminary efficacy of this compound. In specific aim 1, we propose to perform correlative studies (PK and PD) using specimens from the Phase 1 clinical trial of KPT-330 in AML patients with the intent to: 1) identify pretreatment molecular/cytogenetic biomarkers associated with clinical response and drug activity, 2) evaluate PD endpoints and 3) asses the relationship between PK and PD endpoints. Because AML is a clinically and molecularly complex disease that is unlikely to be cured with a single agent, it is likely that to achieve maximal anti-leukemia activity we need to combine KPT-330 with other active regimens in AML. Our group recently reported a relatively effective and non toxic single agent decitabine treatment schedule for older AML patients. Our preliminary data support that priming AML blasts with decitabine increases KPT-330 anti-leukemic effects. We hypothesize that this effect is caused by the nuclear accumulation of TS previously induced by decitabine. In specific aim 2, we propose to conduct a Phase 1 clinical trial of decitabine followed by KPT-330 in newly diagnosed unfit elderly (>60) or refractory/relapsed AML patients in order to determine: 1) the safety and tolerability of the regimen; 2) the Phase 2 recommended dose; 3) preliminary efficacy and 4) PD endpoints including CRM1 dependent targets expression, methylome, transcriptome and miRNA profiling using next generation sequencing. Last, since treatment with CRM1 inhibitors results in up-regulation and nuclear accumulation of p53 and Topoisomerase (Topo) IIα (a key enzyme that is required for Topo II inhibitors to induce DNA-cleavage complexes and cell death) in AML blasts, we hypothesize that restoring p53 expression and nuclear localization of Topo II� may increase chemotherapy sensitivity to cytarabine/topo II inhibitors in refractory/relapsed AML blasts. Our data support the hypothesis that KPT-330 synergizes with cytarabine and idarubicin. In specific aim 3 we propose to overcome chemotherapy resistance in refractory/relapsed AML blasts by enhancing cytarabine and/or Topo IIα inhibitors anti-leukemic effects using concomitant or sequential treatment with KPT-330. The main goal of this proposal is to develop oral CRM1 Inhibitors treatment for AML.

描述（由申请人提供）：急性髓系白血病（AML）的预后较差，凸显了对新型治疗方法的迫切需求。CRM 1是一种核输出受体，参与肿瘤抑制因子（TS）[例如p53]主动转运出细胞核，导致其失活。CRM 1蛋白的过表达已在AML中描述。使用口服选择性抑制剂靶向CRM 1导致p53的显著核积累，进而导致AML细胞系和患者胚细胞中的高度凋亡、细胞周期停滞和髓样分化。基于这些初步数据，我们假设CRM 1抑制剂将是安全和耐受的，并将在AML患者中显示单药抗白血病活性。在难治性/复发性和新诊断的不适合的老年（>65岁）AML中开始KPT-330（最后一代口服CRM 1抑制剂）的I期研究，目的是评估该化合物的安全性、耐受性和初步功效。在具体目标1中，我们建议使用AML患者中KPT-330 I期临床试验的标本进行相关研究（PK和PD），目的是：1）鉴定与临床应答和药物活性相关的治疗前分子/细胞遗传学生物标志物，2）评价PD终点，3）评估PK和PD终点之间的关系。由于AML是一种临床和分子上复杂的疾病，不太可能用单一药物治愈，因此为了达到最大的抗白血病活性，我们可能需要将联合收割机KPT-330与AML中的其他活性方案组合。我们的小组最近报道了一个相对有效的和无毒的单药地西他滨治疗方案，老年AML患者。我们的初步数据支持用地西他滨引发AML原始细胞增加KPT-330抗白血病作用。我们推测，这种影响是由先前由地西他滨诱导的TS核积聚引起的。在具体目标2中，我们建议在新诊断的不适合的老年（>60）或难治性/复发性AML患者中进行地西他滨随后KPT-330的I期临床试验，以确定：1）方案的安全性和耐受性; 2）II期推荐剂量; 3）初步疗效和4）PD终点，包括CRM 1依赖性靶标表达、甲基化组、转录组和使用下一代测序的miRNA谱分析。最后，由于CRM 1抑制剂治疗导致AML母细胞中p53和拓扑异构酶（Topo）IIα（Topo II抑制剂诱导DNA切割复合物和细胞死亡所需的关键酶）的上调和核积累，我们假设恢复p53表达和Topo II β的核定位可能会增加难治性/复发性AML母细胞对阿糖胞苷/Topo II抑制剂的化疗敏感性。我们的数据支持KPT-330与阿糖胞苷和依达拉奉协同作用的假设。在具体目标3中，我们提出通过使用KPT-330伴随或序贯治疗增强阿糖胞苷和/或Topo IIα抑制剂的抗白血病作用，克服难治性/复发性AML原始细胞的化疗耐药性。该提案的主要目标是开发用于AML的口服CRM 1抑制剂治疗。