Targeted inhibition of angiogenesis in myelodysplastic s

描述(由申请人提供) MDS代表了一些最常见的血液系统恶性肿瘤，具有 发病率与慢性淋巴细胞性白血病相近。给定 美国人口老龄化和缺乏有效的标准 对于这些疾病的治疗，MUDS患者的管理已经成为 问题越来越多。MDS具有以下显著特征： 无效的造血和增加白血病转化的风险。 最近的研究表明，这些疾病表现出骨骼的增加。 骨髓(EM)微血管密度，其大小直接相关 以成髓细胞百分比表示。我们已经证明血管内皮细胞的生长 血管内皮生长因子及其受体由粒单核细胞前体细胞表达 MDS和急性髓系白血病(AML)，以及血管内皮生长因子的阐述 有助于抑制承诺的祖细胞生长和过量的骨髓 产生肿瘤坏死因子α。用具有血管内皮生长因子受体活性的KG-1 AML细胞作为靶细胞 模型，我们研究了血管内皮生长因子在急性髓系白血病细胞中的生物学效应。 包括抑制NE-B核转位、刺激白血病 通过与FIT-1或KDR血管内皮生长因子受体相互作用进行自我更新， 和激活磷酸肌醇-3-激酶/Akt信号通路。我们 建议修改细胞内血管内皮生长因子精细表达或血管内皮生长因子受体的药物 信号会损害白血病祖细胞的自我更新，降低对 成熟信号，抑制炎性细胞因子的产生，并促进 MDS患者的造血功能更为有效。我们为描绘血管内皮生长因子所做的努力 AML祖细胞中的受体信号通路提供了一个独特的机会 验证体内靶点抑制作为其生物活性的终点 新的治疗方法。在这个项目中，我们将调查三个具体目标 评估抑制血管内皮细胞生长因子或其活性的新疗法 MDS患者的受体信号转导及其相互关系 体内靶点抑制与生物学和血液学终点之间的关系。这个 这项建议的具体目的是：1)确定 血管内皮生长因子抑制剂沙利度胺与MDS的关系 靶抑制和血液学反应之间的关系。2)调查 血管内皮生长因子受体酪氨酸激酶的分子和药理作用 抑制剂SU-5416，在体外和动物模型中。 3)检测SU-5416对MDS患者的生物学效应。 血液学反应与血管内皮生长因子受体酪氨酸激酶的关系 临床标本中的抑菌作用。

Description (provided by applicant) The MDSs represent some of the most common hematologic malignancies, with an incidence that approximates that for chronic lymphocytic leukemia. Given the aging of the United States population and the absence of a standard effective treatment for these disorders, management of patients with MUDS has become increasingly problematic. The MDSs share the distinguishing features of ineffective hematopoiesis and increased risk of leukemia transformation. Recent studies have shown that these disorders display an increase in bone marrow (EM) microvessel density, the magnitude of which directly correlates with myeloblast percentage. We have shown that vascular endothelial growth factor (VEGF) and its receptors are expressed by myelomonocytic precursors in MDS and acute myelogenous leukemia (AML), and that VEGF elaboration contributes to suppression of committed progenitor growth and excess medullary generation of TNF alpha. Using the VEGF-receptor competent KG-1 AML cells as a model, we have characterized the biologic effects of VEGF in AML cells, which include suppression of nuclear translocation of NE-B, stimulation of leukemia self renewal via interaction with either of the Fit-1 or KDR VEGF receptors, and activation of the phosphoinositol-3-kinase/Akt signaling pathway. We propose that agents which modify cellular VEGF elaboration or VEGF receptor signaling will impair leukemia progenitor self renewal, lower resistance to maturation signals, impair generation of inflammatory cytokines, and promote more effective hematopoiesis in MDS. Our efforts to delineate the VEGF receptor signaling pathway in AML progenitors provides a unique opportunity to validate in vivo target inhibition as an endpoint for biologic activity of novel therapeutics. In this project, we will investigate three Specific Aims that evaluate novel therapeutics which inhibit the actions of VEGF or its receptor signaling in patients with MDS, and delineate the relationship between in vivo target inhibition, and biologic and hematologic endpoints. The Specific Aims of this proposal are: 1) To determine the biologic effects of the VEGF inhibitor, thalidomide, in patients with MDS, and the relationship between target inhibition and hematologic response. 2) To investigate the molecular and pharmacologic effects of the VEGF receptor tyrosine kinase inhibitor, SU-5416, in vitro and in animal models. 3)To determine the biological effects of SU-5416 in patients with MDS, and the relation between hematologic response and VEGF -receptor tyrosine kinase inhibition in clinical specimens.