Acquired Resistance to VEGF blockade in Wilms tumor

描述（由申请人提供）：虽然大多数患有Wilms肿瘤（WT）的儿童都治愈了，但有一部分患有侵袭性疾病的儿童仍然无法接受目前的所有治疗。本文主要研究血管内皮生长因子（VEGF）在WT血管生成中的作用。我们的总体策略将是在异种移植模型中表征对VEGF状态改变的反应，重点关注内皮、募集的血管周围细胞和血管生成相关基因（VEGF、血管生成素、血小板衍生生长因子- b （PDGF-B）和Eph/Ephrins）表达的变化。我们的初步结果表明，VEGF阻断最初抑制WT异种细胞生长和血管生成。然而，长期治疗导致肿瘤复发生长，尽管持续的VEGF阻断，与血管系统的深刻改变有关。我们假设这种明显抵抗的潜在机制是肿瘤血管的重塑，使其不太依赖VEGF功能。我们将通过研究有助于动脉/静脉规范、血管完整性和重塑的基因（目的1和2）和可能有助于WT对VEGF阻断反应的her2/neu癌基因（目的3）来研究这一机制。在Aim 1中，我们假设VEGF与ephrins、血管生成素和PDGFB合作，在形成具有支持WT侵袭行为的特定特征的血管系统中起着关键作用。我们将研究不同组织学异种移植物对VEGF阻断或过表达的反应，将肿瘤状态与血管结构变化和血管生成相关基因的表达联系起来。我们将确定VEGF阻断是否会改变血管的特定属性。在Aim 2中，我们假设PDGF-B有助于WT异种移植物对VEGF阻断的获得性抵抗。我们将在Wilms肿瘤中过表达和阻断PDGF-B，并描述PDGF-B状态改变对VEGF拮抗反应的影响。在Aim 3中，我们将通过比较在表达不同水平VEGF受体的异种移植物中阻断的效果，来确定her2/neu表达是否在VEGF阻断期间具有相对的生存优势。我们将描述her2/neu激活和阻断对体外肿瘤血管生成基因和体内血管生成基因的影响，并确定her2/neu抑制是否影响对VEGF拮抗剂的抗性获得。由此得出的临床前数据可能为在Wilms肿瘤中使用抗血管生成疗法提供合理的依据，并有助于规避其局限性。

DESCRIPTION (provided by applicant): While most children with Wilms tumor (WT) are cured, a subset with aggressive disease continues to fail all current therapies. This proposal focuses on the role of vascular endothelial growth factor (VEGF) in WT angiogenesis. Our general strategy will be to characterize the response to altered status of VEGF in a xenograft model, focusing on changes in endothelium, recruited perivascular cells, and expression of angiogenesis-related genes (VEGF, angiopoietins, platelet-derived growth factor-B (PDGF-B), and Eph/Ephrins). Our preliminary results demonstrate that VEGF blockade initially inhibits WT xenografl growth and angiogenesis. However, prolonged treatment leads to recurrent tumor growth despite continued VEGF blockade, associated with profound alterations in vasculature. We hypothesize that a potential mechanism of this apparent resistance is the remodeling of tumor vessels to a state where they are less dependent on VEGF function. We will examine this mechanism by studying genes contributing to arterial/venous specification, vascular integrity, and remodeling (Aims 1 and 2) and the her2/neu oncogene, which may contribute to WT response to VEGF blockade (Aim 3). In Aim 1, we hypothesize that VEGF, in cooperation with ephrins, angiopoietins, and PDGFB, plays a critical role in forming vasculature with specific features that support aggressive behavior in WT. We will examine the response to VEGF blockade or overexpression in developing xenografts of different histology, relating tumor status to changes in vessel structure and expression of angiogenesis-related genes. We will determine if the regression of established vessel networks by VEGF blockade will alter specific vascular attributes. In Aim 2, we hypothesize that PDGF-B contributes to acquired resistance of WT xenografts to VEGF blockade. We will overexpress and block PDGF-B in Wilms tumor, and characterize the effect of altered status of PDGF-B on the response to VEGF antagonism. In Aim 3, we will determine whether her2/neu expression confers a relative survival advantage during VEGF blockade, by comparing the effects of blockade in xenografts expressing different levels of this receptor. We will characterize the effects of her2/neu activation and blockade on angiogenic genes in tumors in vitro and angiogenesis in vivo, and determine whether her2/neu inhibition affects acquisition of resistance to VEGF antagonists. The resulting preclinical data may provide a rational basis for use of anti-angiogenic therapies in Wilms tumor, and assist in circumventing their limitations.