Acquired Resistance to VEGF blockade in Wilms tumor

描述(申请人提供)：虽然大多数肾母细胞瘤(WT)的儿童都被治愈了，但有一部分患有侵袭性疾病的儿童仍然无法通过目前的所有治疗。本研究重点探讨血管内皮生长因子(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血管内皮生长因子状态改变的反应，重点是内皮细胞的变化，血管周围细胞的招募，以及血管生成相关基因的表达(血管内皮生长因子、血管生成素、血小板衍生生长因子-B(PDGF-B)和Eph/Ephins)。我们的初步结果表明，阻断血管内皮生长因子最初抑制异种移植瘤的生长和血管生成。然而，尽管持续阻断血管内皮生长因子，但长期治疗会导致肿瘤复发，并伴随着血管系统的深刻变化。我们假设，这种明显的耐药性的一个潜在机制是肿瘤血管重塑到一种对血管内皮生长因子功能依赖较少的状态。我们将通过研究参与动脉/静脉规范、血管完整性和重塑的基因(目标1和2)以及HER2/neu癌基因来研究这一机制，HER2/neu癌基因可能有助于WT对血管内皮生长因子阻断的反应(目标3)。在目标1中，我们假设，血管内皮生长因子与肾上腺素、血管生成素和PDGFB一起，在形成具有支持WT攻击行为的特定特征的血管系统中发挥关键作用。我们将检查不同组织学异种移植中对血管内皮生长因子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。我们将确定血管内皮生长因子阻滞剂对已建立的血管网络的逆转是否会改变特定的血管属性。在目标2中，我们假设PDGF-B参与了WT移植对血管内皮生长因子阻断的获得性抵抗。我们将在肾母细胞瘤中过表达和阻断PDGF-B，并研究PDGF-B状态改变对血管内皮生长因子拮抗反应的影响。在目标3中，我们将通过比较表达不同水平HER2/neu受体的异种移植的效果，来确定HER2/neu的表达是否在血管内皮生长因子阻断期间提供了相对的生存优势。我们将研究HER2/neu的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，并确定抑制HER2/neu是否会影响对血管内皮生长因子拮抗剂的耐药性。由此产生的临床前数据可能为在肾母细胞瘤中使用抗血管生成治疗提供合理的基础，并有助于绕过其局限性。

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.