Targeted inhibition of angiogenesis in myelodysplastic s

说明（申请人提供） MDS代表了一些最常见的血液恶性肿瘤， 发病率接近慢性淋巴细胞白血病。鉴于 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患者的管理已成为 越来越成问题。MDS具有以下显著特征： 无效造血和增加白血病转化的风险。 最近的研究表明，这些疾病显示骨增加， 骨髓（EM）微血管密度，其大小直接相关 与成髓细胞百分比。我们已经证明血管内皮生长 VEGF及其受体由骨髓单核细胞前体表达， MDS和急性髓性白血病（AML），并认为VEGF的阐述 有助于抑制定向祖细胞生长和过量的骨髓 TNF α的产生。使用VEGF受体感受态KG-1 AML细胞作为对照， 模型，我们已经描述了VEGF在AML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 VEGF受体相互作用进行自我更新， 和磷酸肌醇-3-激酶/Akt信号通路的激活。我们 提出修饰细胞VEGF加工或VEGF受体的试剂 信号传导将损害白血病祖细胞的自我更新，降低对 成熟信号，损害炎性细胞因子的产生，并促进 更有效的造血功能我们努力描绘血管内皮生长因子 AML祖细胞中的受体信号通路提供了独特的机会， 验证体内靶向抑制作为生物活性的终点 新疗法。在这个项目中，我们将研究三个具体目标 其评价了抑制VEGF或其受体的作用的新的治疗剂， MDS患者的受体信号，并描绘关系 体内靶向抑制与生物学和血液学终点之间的差异。的 本建议的具体目的是：1）确定 VEGF抑制剂沙利度胺在MDS患者中的作用， 靶点抑制和血液学反应之间的联系2)探讨 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的作用。 3）研究SU-5416对MDS患者的生物学效应， 血液学反应与VEGF受体酪氨酸激酶的关系 临床标本中的抑制。

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.