Bortezomib and Idarubicin in the Treatment of AML

硼替佐米和伊达比星治疗 AML

• 批准号: 6887118
• 负责人: Dianna S Howard
• 金额: $ 25.76万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-20 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6887118
• 关键词: acute myelogenous leukemia; adult human (21+); anthracyclines; antineoplastics; apoptosis; clinical research; clinical trial phase I; clinical trial phase II; combination chemotherapy; dosage; drug screening /evaluation; human old age (65+); human subject; human therapy evaluation; neoplasm /cancer chemotherapy; neoplasm /cancer relapse /recurrence; nuclear factor kappa beta; p53 gene /protein; patient oriented research; protease inhibitor; proteasome

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is a clonal, malignant disease of hematopoietic cells, characterized by the proliferation of abnormal blast cells and impaired hematopoiesis. While younger patients with favorable cytogenetics have increasingly favorable outcomes with dose intensive chemotherapy, they represent a distinct minority of patients with this disease. Patients with unfavorable cytogenetics, advanced age (>=60), and antecedent hematologic disorders have a decreased incidence of complete remission; even in those who achieve an initial remission, the majority relapse and survival is poor. Clearly this is a patient population for whom novel therapies are needed. Studies from our laboratory have demonstrated that the combination of the proteasome inhibitor, bortezomib, with the anthracycline, idarubicin, at concentrations readily achievable in vivo can rapidly induce apoptosis in primary human AML cells in vitro. Studies from our laboratory have demonstrated that apoptosis induced in this fashion correlates with several specific changes in primary AML cells. Following treatment with bortezomib and idarubicin strong inhibition of NF-kappaB is rapidly observed, indicating inhibition of important survival signals. In addition, levels of p53 protein are strongly increased in treated AML cells, suggesting p53 mediated changes in gene expression might be involved in the apoptosis induced by this combination. Based on our observations we propose a phase I and II clinical trial with the novel agent, bortezomib, and idarubicin given to newly diagnosed, elderly or relapsed AML patients. Monitoring for in vivo induction of apoptosis, as well as, important correlative studies assaying for inhibition of NF-kappaB and increased p53 expression are proposed. We anticipate that with this novel treatment regimen we will observe potent anti-leukemic activity and complete clinical remissions.

描述（由申请人提供）：急性髓性白血病（AML）是一种造血细胞的克隆性恶性疾病，其特征为异常母细胞增殖和造血功能受损。虽然具有良好细胞遗传学的年轻患者在剂量强化化疗中具有越来越有利的结果，但他们代表了患有这种疾病的患者的明显少数。细胞遗传学不良、高龄（>=60岁）和既往有血液学疾病的患者完全缓解的发生率较低;即使在那些达到初始缓解的患者中，大多数复发和生存率也很差。显然，这是一个需要新疗法的患者群体。我们实验室的研究已经证明，蛋白酶体抑制剂硼替佐米与蒽环类药物伊达司琼在体内容易达到的浓度下的组合可以在体外快速诱导原代人AML细胞的凋亡。我们实验室的研究表明，以这种方式诱导的细胞凋亡与原代AML细胞中的几种特定变化相关。在用硼替佐米和艾达鲁肽处理后，迅速观察到NF-κ B的强烈抑制，表明重要的存活信号的抑制。此外，p53蛋白的水平在治疗的AML细胞中强烈增加，表明p53介导的基因表达的变化可能参与了这种组合诱导的细胞凋亡。根据我们的观察，我们提出了一项I期和II期临床试验，新的药物，硼替佐米，伊达比林给予新诊断的，老年或复发的AML患者。监测体内诱导的细胞凋亡，以及重要的相关研究分析抑制NF-κ B和增加p53的表达提出。我们预计，采用这种新的治疗方案，我们将观察到有效的抗白血病活性和完全的临床缓解。