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: 7243396
• 负责人: JESSICA J KANDEL
• 金额: $ 31.04万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7243396
• 关键词: Adult; Affect; Affinity; Aggressive behavior; Angiogenic Factor; Angiopoietin-1; Angiopoietins; Apoptosis; Behavior; Blood Vessels; Caliber; Cells; Child; Chronic; Clinical Trials; Complex; Data; Disease; Disease regression; Endothelium; Environment; Eph Family Receptors; Ephrins; Exhibits; Family; Gene Expression; Genes; Genetic Heterogeneity; Goals; Growth; Growth Factor Inhibition; Histology; In Vitro; Kidney; Link; Maintenance; Malignant Neoplasms; Mediator of activation protein; Modeling; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Nephroblastoma; Oncogenes; PDGFB gene; Patients; Pericytes; Play; Protein Overexpression; Proto-Oncogene Proteins c-sis; Recruitment Activity; Recurrence; Recurrent tumor; Relative (related person); Research Personnel; Resistance; Role; Signal Transduction; Stress; Structure; Testing; Time; Tumor Angiogenesis; Up-Regulation; VEGFA gene; Vascular Endothelial Growth Factors; Venous; Xenograft Model; Xenograft procedure; angiogenesis; antiangiogenesis therapy; base; gene function; in vivo; neoplastic cell; novel; novel strategies; pre-clinical; programs; receptor; resistance mechanism; response; tumor; tumor growth; tumor xenograft

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Wilms肿瘤（WT）的儿童已经治愈，但患有侵略性疾病的子集仍使所有当前疗法都失败。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。我们的一般策略将是表征对异种移植模型中VEGF状态改变的反应，重点是内皮的变化，募集的周围血管周围细胞以及血管生成相关基因（VEGF，Angiopoietins，血小板生长因子B（PDGF-B（PDGF-B）（PDGF-B）和EPH/EPH/EPH/EPHRINS）的表达。我们的初步结果表明，VEGF阻滞最初抑制WT Xenografl生长和血管生成。然而，尽管VEGF持续阻断，但长期治疗导致肿瘤的复发性生长，这与脉管系统的深刻变化有关。我们假设这种明显电阻的潜在机制是将肿瘤血管重塑到较少依赖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（AIMS 1和2）和HER2/NEU癌基的基因来检查这种机制，这可能有助于WT对VEGF阻断的反应（AIM 3）。在AIM 1中，我们假设VEGF与Ephrins，Angiopoietins和PDGFB合作，在形成脉管系统的特定特征方面起着至关重要的作用。我们将研究对不同组织学的异种移植物中对VEGF阻滞或过表达的反应，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有关。我们将确定通过VEGF封锁对已建立的血管网络的回归是否会改变特定的血管属性。在AIM 2中，我们假设PDGF-B有助于WT异种移植对VEGF阻滞的获得性。我们将过表达并阻止Wilms肿瘤中的PDGF-B，并表征PDGF-B状态改变对VEGF拮抗作用的影响的影响。在AIM 3中，我们将通过比较表达该受体不同水平的异种移植物中的封锁作用来确定HER2/neu表达在VEGF封锁过程中是否具有相对的生存优势。我们将表征HER2/NEU激活和阻断体内肿瘤中血管生成基因的影响，并确定HER2/NEU抑制是否会影响对VEGF拮抗剂的抗性的获得。由此产生的临床前数据可能为使用抗血管生成疗法在Wilms肿瘤中提供合理的基础，并协助避免其局限性。