Acquired Resistance to VEGF blockade in Wilms tumor

描述（由申请人提供）：虽然大多数肾母细胞瘤（WT）儿童被治愈，但侵袭性疾病的一个子集继续失败，所有目前的治疗。该建议的重点是血管内皮生长因子（VEGF）在WT血管生成中的作用。我们的总体策略将是描述异种移植模型中对VEGF状态改变的反应，重点关注内皮细胞、募集的血管周围细胞和血管生成相关基因（VEGF、血管生成素、血小板源性生长因子-B（PDGF-B）和Eph/Ephrin）的表达变化。我们的初步结果表明，VEGF阻断最初抑制WT异种移植物生长和血管生成。然而，尽管持续的VEGF阻断，延长的治疗导致复发性肿瘤生长，与血管系统的深刻改变相关。我们推测，这种明显的阻力的一个潜在机制是肿瘤血管重塑到一个状态，他们是不太依赖于VEGF功能。我们将通过研究有助于动脉/静脉特化、血管完整性和重塑的基因（目的1和2）以及可能有助于WT对VEGF阻断的反应的her 2/neu癌基因（目的3）来研究这种机制。在目的1中，我们假设VEGF与肝配蛋白、血管生成素和PDGFB合作，在形成具有支持WT攻击行为的特定特征的血管系统中起关键作用。我们将研究不同组织学的异种移植物对VEGF阻断或过度表达的反应，将肿瘤状态与血管结构和血管生成相关基因表达的变化联系起来。我们将确定通过VEGF阻断建立的血管网络的回归是否会改变特定的血管属性。在目的2中，我们假设PDGF-B有助于WT异种移植物对VEGF阻断的获得性抗性。我们将在肾母细胞瘤中过表达和阻断PDGF-B，并描述PDGF-B状态改变对VEGF拮抗作用的影响。在目标3中，我们将通过比较表达不同水平该受体的异种移植物中的阻断效果，确定her 2/neu表达是否在VEGF阻断期间赋予相对存活优势。我们将描述her 2/neu激活和阻断对体外肿瘤血管生成基因和体内血管生成的影响，并确定her 2/neu抑制是否影响对VEGF拮抗剂的耐药性。由此产生的临床前数据可能提供了一个合理的基础上使用抗血管生成疗法在肾母细胞瘤，并协助规避其局限性。

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.