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（由适用提供）：急性髓样白血病（AML）的预后很差，强调了对新型治疗方法的迫切需求。 CRM1是参与肿瘤补充剂（TS）主动运输的核出口接收器[例如p53]出于核导致其失活。 AML中已经描述了CRM1蛋白的过表达。使用口服选择性抑制剂靶向CRM1导致p53的核积累，进而在AML细胞系和患者爆炸中高度高度凋亡，细胞周期停滞和髓样分化。基于这些初步数据，我们假设CRM1抑制剂将是安全和耐受性的，并将显示AML患者中的单药抗白血病活性。在特定目的1中，对难治性/复发和新诊断的耐火/复发和新诊断的KPT-330（最后一代口服CRM1抑制剂）的1阶段研究在特定目标1中，我们提议使用与AML的bi/biect norter cy nor相关的1摩尔相关的临床试验进行相关性研究（PK和PD）：1 mor：1）临床反应和药物活性，2）评估PD终点和3）PK和PD端点之间的关系。由于AML是一种临床和分子复杂的疾病，不太可能与单一药物治愈，因此，要实现最大的抗白血病活性，我们需要将KPT-330与AML中的其他活性方案相结合。我们的小组最近报告了年龄较大AML患者的相对有效和无毒的单药决策治疗计划。我们的初步数据支持启动AML爆炸decideabine会增加KPT-330抗白血病效应。我们假设这种作用是由先前由Decideabine引起的TS的核积累引起的。在特定的目标2中，我们建议在新诊断的新诊断（> 60）或难治/复发的AML患者中进行Decideabine，然后进行KPT-330进行1期临床试验，以确定：1）该方案的安全性和耐受性； 2）第二阶段建议的剂量； 3）初步效率和4）PD端点，包括使用下一代测序的CRM1依赖性目标表达，甲基化组，转录组和miRNA分析。最后，由于用CRM1抑制剂治疗会导致p53和topoisomerase（topo）IIα的上调和核积累（TOPO II II抑制剂是诱导DNA - 裂解复合物和细胞死亡所必需的关键酶）在AML爆炸中，我们在恢复P53表达和核核位置的AML爆炸中，我们假设。可能会增加对难治性/复发AML爆炸中细胞押滨/topo II抑制剂的化学疗法敏感性。我们的数据支持KPT-330与细胞蛋白滨和伊达比辛合成的假设。在特定的目标3中，我们建议通过使用KPT-330的伴随或顺序治疗，通过增强Cytarabine和/或TOPOIIα抑制剂抗白血病效应来克服难治性/复发AML爆炸中的化学疗法抗性。该提案的主要目标是开发口服CRM1抑制剂治疗AML。