Arsenic Trioxide Down-Regulates STAT3 Activity in AML

描述(申请人提供)：急性髓系白血病(AML)原始细胞需要造血生长因子才能存活。生长因子通过信号转导和转录激活蛋白(STAT)介导信号转导。我们已经证明，在大约50%的AML病例诊断时，STATS被结构性激活。具有组成性STAT3活性的原始细胞具有独特的基因图谱，并能抵抗细胞凋亡。我们已经证明，与不具有结构性STAT3活性的患者相比，具有结构性STAT3活性的患者的无病生存期显著缩短。这项研究中的大多数患者都接受了我们内部的临床试验，使用了大剂量的阿糖胞苷和伊达比星。三氧化二砷(ATO)对急性早幼粒细胞白血病具有生长抑制活性。在其他类型的AML中，ATO诱导细胞凋亡，导致ATO被指定为AML的孤儿药物。然而，ATO的确切作用机制尚不清楚。我们发现ATO下调AML细胞系中STAT3的组成性活性。我们假设ATO类似地下调AML患者原始细胞中的STAT3，从而增强他们对细胞凋亡的敏感性。我们建议测量ATO体内治疗期间AML原始细胞中STAT3活性的基线和变化。我们将通过对60岁新诊断的急性髓系白血病患者进行ATO的I期研究来实现这一目标。在新诊断的AML患者中，ATO给药超过1小时，然后是大剂量阿糖胞苷和伊达比星。在本研究中，我们将确定ATO的最大耐受量，并研究体内给予ATO对AML细胞STAT3活性、诱导凋亡和基因表达谱变化的影响。此外，我们将尝试确定ATO控制STAT3活性的方式，以及这种影响如何改变基因图谱并诱导细胞凋亡。

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.