Arsenic Trioxide Down-Regulates STAT3 Activity in AML

三氧化二砷下调 AML 中的 STAT3 活性

• 批准号: 6648141
• 负责人: MEIR WETZLER
• 金额: $ 38.59万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-20 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6648141
• 关键词: acute myelogenous leukemia; antineoplastics; apoptosis; arsenic; cell line; clinical research; clinical trial phase I; dosage; drug screening /evaluation; gene expression; genetic regulation; genetic transcription; hematopoietic growth factor; human subject; human therapy evaluation; lymphoblast; metal oxide; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; patient oriented research; protein isoforms; transcription factor

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) blasts require hematopoietic growth factors for their survival. Growth factors mediate signal transduction through signal transducer and activator of transcription (STAT) proteins. We have demonstrated that STATs are constitutively activated in approximately 50% of AML cases at diagnosis. Blasts with constitutive STAT3 activity have a unique gene profile and are resistant to apoptosis. We have shown that disease-free survival is significantly shorter in patient with, compared to without, constitutive STAT3 activity. Most of the patients in this study were treated with our in-house clinical trial using high-dose cytarabine and idarubicin. Arsenic trioxide (ATO) has growth suppressing activity in acute promyelocytic leukemia. In other types of AML, ATO induces apoptosis, leading to designation of ATO as an orphan drug for AML. However, the precise mechanisms of action of ATO are unknown. We have discovered that ATO down-regulates constitutive STAT3 activity in AML cell lines. We hypothesize that ATO similarly down-regulates STAT3 in blasts from AML patients and thus enhances their sensitivity to undergo apoptosis. We propose to measure the baseline and changes in STAT3 activity in AML blasts during in vivo therapy with ATO. We will accomplish this goal by performing a phase I study of ATO administered over one hour followed by high-dose cytarabine and idarubicin in patients with newly diagnosed AML < 60 years old. We will determine the maximum tolerated dose of ATO in this study and study the effects of in vivo administration of ATO on STAT3 activity, induction of apoptosis and changes in gene expression profiles in AML cells. In addition, we will attempt to identify the mode by which ATO controls the activity of STAT3 and how this effect alters the gene profile patterns and induces apoptosis.

描述（由申请人提供）：急性髓性白血病（AML）原始细胞需要造血生长因子才能生存。生长因子通过信号转导子和转录激活子（STAT）蛋白介导信号转导。我们已经证明，STAT在大约50%的AML病例中在诊断时被组成性激活。具有组成性STAT3活性的胚细胞具有独特的基因谱并且对细胞凋亡具有抗性。我们已经证明，与没有组成性STAT3活性的患者相比，具有组成性STAT3活性的患者的无病生存期显著较短。本研究中的大多数患者均接受了我们的内部临床试验，使用高剂量阿糖胞苷和依达鲁肽进行治疗。三氧化二砷（ATO）对急性早幼粒细胞白血病有生长抑制作用。在其他类型的AML中，ATO诱导细胞凋亡，导致ATO被指定为AML的孤儿药。然而，ATO的确切作用机制尚不清楚。我们已经发现ATO下调AML细胞系中的组成型STAT3活性。我们假设ATO同样下调AML患者原始细胞中的STAT3，从而增强其对细胞凋亡的敏感性。我们建议在使用ATO的体内治疗期间测量AML原始细胞中STAT3活性的基线和变化。我们将通过在60岁以下新诊断的AML患者中进行ATO给药1小时以上，随后进行高剂量阿糖胞苷和依达替尼的I期研究来实现这一目标。我们将在本研究中确定ATO的最大耐受剂量，并研究ATO体内给药对AML细胞中STAT3活性、诱导凋亡和基因表达谱变化的影响。此外，我们将试图确定ATO控制STAT3活性的模式，以及这种作用如何改变基因谱模式并诱导细胞凋亡。