VEGF blockade and alternative angiogenic pathways in neuroblastoma

神经母细胞瘤中的 VEGF 阻断和替代血管生成途径

• 批准号: 7463093
• 负责人: DARRELL J YAMASHIRO
• 金额: $ 33.41万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-10 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7463093
• 关键词: Adult; Angiogenesis Inhibitors; Architecture; Binding; Blood Vessels; Cell Line; Cell Survival; Child; Clinical; Crossbreeding; Data; Development; Diagnosis; Disease; Endothelial Cells; Genetic Models; Goals; Growth; Human; Implant; In Vitro; Kidney; Lead; Ligands; Malignant Neoplasms; Mus; Neuroblastoma; Nude Mice; PGF gene; Pathologic Neovascularization; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Pilot Projects; Placental Growth Factor; Protein Overexpression; Proteins; Public Health; Reporting; Resistance; Role; Signal Transduction; Staging; TAN-1 protein; Testing; Transcriptional Activation; Tube; Tumor-Derived; Up-Regulation; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascular Endothelium; Work; Xenograft Model; Xenograft procedure; angiogenesis; concept; experience; in vivo Model; infancy; inhibitor/antagonist; knock-down; neoplastic cell; notch protein; novel; outcome forecast; preclinical study; receptor; research study; response; secretase; tumor; tumor growth; tumor vascular supply

DESCRIPTION (provided by applicant): Most children diagnosed with neuroblastoma after infancy have a poor prognosis, and few will survive despite intensive therapy. New treatments are urgently needed. Recently, drugs which block blood vessel growth (angiogenesis) into tumors have been clinically validated in adults, and may offer promise for these patients. One validated anti-angiogenic target is vascular endothelial growth factor (VEGF), which is expressed in essentially all human cancers, including neuroblastoma. VEGF can bind to both VEGF-receptor-1 (VEGFR1) and VEGFR2, but much prior work indicates that VEGF stimulates angiogenesis primarily via VEGFR2. Therefore, antagonism of VEGF/VEGFR2 signaling has been the principal approach tested against experimental and human cancers. We have previously demonstrated that drugs which block VEGF and VEGFR2 lessen angiogenesis and growth of experimental early-stage neuroblastoma tumors, suggesting that this therapy may be therapeutically useful in children with this cancer. However, our experiments also demonstrate that these tumors ultimately become resistant to VEGF/VEGFR2 blockade. These results suggest that an alternative mechanism may support angiogenesis in neuroblastoma when VEGF/ VEGFR2 signaling is blocked. In these studies, we will determine if activation of VEGFR1 and Notch pathways in neuroblastoma tumor vessels constitutes one such alternative. Both VEGFR1 and Notch proteins are known to contribute to angiogenesis in disease states. In addition, activation of each of these two pathways may stimulate the other. Our initial experiments support this concept, and demonstrate VEGFR1 and Notch activation in the vessels of neuroblastoma tumors that are resistant to anti-VEGF treatment. These observations lead us to propose that one mechanism by which neuroblastomas compensate for anti-VEGF treatment is to preserve tumor blood supply by activating these alternative pathways in vasculature. Utilizing our well-characterized xenograft model, in which NB cell lines are implanted in the kidney of athymic mice, and the TH-MYCN genetic model of NB, we will, in Aim 1, determine whether VEGFR1 signaling can rescue tumor vasculature from VEGFR2 blockade; and in Aim 2, we will determine whether Notch activation in vessels promotes tumor resistance to VEGFR2 blockade. Our overall goal in these studies is to develop effective new treatments children with neuroblastoma by identifying and then overcoming the mechanisms by which these tumors evade inhibition of VEGF. PUBLIC HEALTH RELEVANCE: Children with metastatic neuroblastoma have a poor prognosis with only 30-35% surviving despite intensive therapy. Drugs which block blood vessel growth (angiogenesis) into tumors have been clinically validated in adults, and may offer promise for these patients. Our overall goal in these studies is to develop an effective anti-angiogenic therapy for children with neuroblastoma by identifying and then overcoming the mechanisms by which these tumors evade VEGF-blocking therapies.

描述（由申请人提供）：大多数在婴儿期后被诊断患有神经母细胞瘤的儿童预后不良，尽管经过强化治疗，很少有人能存活。迫切需要新的治疗方法。最近，阻止血管生长（血管生成）进入肿瘤的药物已在成人中得到临床验证，并可能为这些患者带来希望。一种经过验证的抗血管生成靶点是血管内皮生长因子（VEGF），它在几乎所有人类癌症中表达，包括神经母细胞瘤。 VEGF 可以结合 VEGF 受体 1 (VEGFR1) 和 VEGFR2，但许多先前的研究表明 VEGF 主要通过 VEGFR2 刺激血管生成。因此，拮抗 VEGF/VEGFR2 信号传导已成为针对实验癌症和人类癌症测试的主要方法。我们之前已经证明，阻断 VEGF 和 VEGFR2 的药物可以减少实验性早期神经母细胞瘤的血管生成和生长，表明这种疗法可能对患有这种癌症的儿童有治疗作用。然而，我们的实验还表明，这些肿瘤最终会对 VEGF/VEGFR2 阻断产生耐药性。这些结果表明，当 VEGF/VEGFR2 信号传导被阻断时，另一种机制可能支持神经母细胞瘤中的血管生成。在这些研究中，我们将确定神经母细胞瘤肿瘤血管中 VEGFR1 和 Notch 通路的激活是否构成此类替代方案之一。已知 VEGFR1 和 Notch 蛋白都有助于疾病状态下的血管生成。此外，这两种途径的激活都可能刺激另一种途径。我们的初步实验支持这一概念，并证明了对抗 VEGF 治疗有抵抗力的神经母细胞瘤肿瘤血管中的 VEGFR1 和 Notch 激活。这些观察结果使我们提出，神经母细胞瘤补偿抗 VEGF 治疗的一种机制是通过激活脉管系统中的这些替代途径来保护肿瘤的血液供应。利用我们充分表征的异种移植模型（其中将 NB 细胞系植入无胸腺小鼠的肾脏）以及 NB 的 TH-MYCN 遗传模型，我们将在目标 1 中确定 VEGFR1 信号传导是否可以从 VEGFR2 阻断中拯救肿瘤脉管系统；在目标 2 中，我们将确定血管中的 Notch 激活是否会促进肿瘤对 VEGFR2 阻断的抵抗。我们这些研究的总体目标是通过识别并克服这些肿瘤逃避 VEGF 抑制的机制，开发治疗儿童神经母细胞瘤的有效新疗法。公共卫生相关性：患有转移性神经母细胞瘤的儿童预后较差，尽管经过强化治疗，仍有 30-35% 的患者存活。阻止血管生长（血管生成）进入肿瘤的药物已在成人中得到临床验证，可能为这些患者带来希望。我们在这些研究中的总体目标是通过识别并克服这些肿瘤逃避 VEGF 阻断疗法的机制，为患有神经母细胞瘤的儿童开发一种有效的抗血管生成疗法。