Acquired Resistance to VEGF blockade in Wilms tumor

肾母细胞瘤对 VEGF 阻断获得性耐药

• 批准号: 6720602
• 负责人: JESSICA J KANDEL
• 金额: $ 32.74万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6720602
• 关键词: Wilms' tumor; angiogenesis; angiopoietins; athymic mouse; gene expression; histology; inhibitor /antagonist; neoplasm /cancer blood supply; neoplasm /cancer genetics; neoplasm /cancer relapse /recurrence; neoplasm /cancer transplantation; neoplastic process; oncogenes; platelet derived growth factor; vascular endothelial growth factors; xenotransplantation

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.

描述（由申请人提供）：虽然大多数患有肾母细胞瘤（WT）的儿童已被治愈，但患有侵袭性疾病的子集仍然无法接受所有当前治疗。该提案重点关注血管内皮生长因子 (VEGF) 在 WT 血管生成中的作用。我们的总体策略是表征异种移植模型中 VEGF 状态改变的反应，重点关注内皮的变化、招募的血管周围细胞以及血管生成相关基因（VEGF、血管生成素、血小板衍生生长因子-B (PDGF-B) 和 Eph/Ephrins）的表达。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，尽管持续阻断 VEGF，但长期治疗仍会导致肿瘤复发，并与脉管系统的深刻改变相关。我们假设这种明显抵抗的潜在机制是肿瘤血管重塑至不太依赖 VEGF 功能的状态。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（目标 1 和 2）以及可能有助于 WT 对 VEGF 阻断的反应的 Her2/neu 癌基因（目标 3）来检查这一机制。在目标 1 中，我们假设 VEGF 与肝配蛋白、血管生成素和 PDGFB 协同作用，在形成具有支持 WT 攻击行为的特定特征的脉管系统中发挥着关键作用。我们将检查不同组织学异种移植物中 VEGF 阻断或过度表达的反应，将肿瘤状态与血管结构的变化和血管生成相关基因的表达联系起来。我们将确定 VEGF 阻断所建立的血管网络的退化是否会改变特定的血管属性。在目标 2 中，我们假设 PDGF-B 有助于 WT 异种移植物对 VEGF 阻断的获得性耐药。我们将在肾母细胞瘤中过度表达和阻断 PDGF-B，并表征 PDGF-B 状态改变对 VEGF 拮抗反应的影响。在目标 3 中，我们将通过比较阻断对表达不同水平的该受体的异种移植物的影响，确定 Her2/neu 表达在 VEGF 阻断期间是否具有相对生存优势。我们将表征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的影响，并确定her2/neu抑制是否影响VEGF拮抗剂耐药性的获得。由此产生的临床前数据可能为肾母细胞瘤中使用抗血管生成疗法提供合理的基础，并有助于规避其局限性。