Effect of Trk Expression and Inhibition in Neuroblastoma

Trk 表达和抑制在神经母细胞瘤中的作用

• 批准号: 6423645
• 负责人: GARRETT M BRODEUR
• 金额: $ 36.7万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-14 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6423645
• 关键词: angiogenesis; apoptosis; biological signal transduction; cell line; chimeric proteins; enzyme activity; enzyme inhibitors; growth factor receptors; neoplasm /cancer genetics; neuroblastoma; neurotrophic factors; protein structure function; protein tyrosine kinase; receptor expression; regulatory gene

DESCRIPTION: (provided by applicant) Neuroblastoma is the most common and deadly solid tumor in children, but this tumor also has a very high propensity to undergo spontaneous differentiation or regression. Evidence suggests that the Trk family of neurotrophin receptors play a critical role in tumor behavior. Neuroblastomas expressing TrkA are biologically favorable and prone to spontaneous differentiation or regression. In contrast, Neuroblastomas expressing TrkB usually have MYCN amplification and are among the most aggressive and deadly tumors known. These tumors also express the TrkB ligand, resulting in an autocrine survival pathway. Unlike the TrkA-expressing tumors, exposure to ligand promotes survival under adverse conditions, but does not cause differentiation. We are exploring the biological basis for the very different behavior of neuroblastomas expressing these highly homologous neurotrophin receptors. We will also determine the consequences of blocking TrkA versus TrkB expressing tumors with the novel, Trk-targeted tyrosine kinase inhibitor CEP-2563. Our specific aims are: Specific Aim 1. Determine the differences in receptor structure, signaling and gene induction that distinguish the biological effects of TrkA versus TrkB expression in human neuroblastoma cells. Hypothesis: A fundamental difference in receptor structure, leading to differences in signaling. Immediate-early gene induction, and/or interactions with P75 explain the difference in biological behavior of TrkA- and TrkB expressing neuroblastomas. Specific Aim 2. Analyze the consequences of TrkA or TrkB inhibition on neuroblastoma behavior and tumorigenicity. Hypothesis: Inhibition of TrkA will induce apoptosis, and inhibition of TrkB will decrease angiogenesis, tumorigenicity and resistance to chemotherapy. The successful completion of these studies should explain why the biological consequences of expressing TrkA versus TrkB are so different, and what portion of the receptor is responsible for this difference. We will also determine the efficacy of the novel tyrosine kinase inhibitor CEP-2563 in treating TrkA and TrkB expressing tumors. Given the increasing evidence for a role of Trk receptors in a variety of pediatric and adult tumors, these data would argue strongly for the utility of Trk receptor inhibition in therapy, alone or in combination.

描述：（由申请人提供）神经母细胞瘤是最常见和最常见的 儿童致命的实体瘤，但这种肿瘤也有很高的倾向 进行自发分化或回归。有证据表明 神经营养素受体 Trk 家族在肿瘤中发挥关键作用 行为。表达 TrkA 的神经母细胞瘤在生物学上是有利的且易于发生 自发分化或回归。相比之下，神经母细胞瘤 表达 TrkB 通常具有 MYCN 扩增，并且是最常见的 已知具有侵袭性和致命性的肿瘤。这些肿瘤还表达 TrkB 配体， 导致自分泌生存途径。与表达 TrkA 的肿瘤不同， 暴露于配体可促进不利条件下的生存，但不会 造成分化。我们正在探索这一现象的生物学基础 表达这些高度同源性的神经母细胞瘤的不同行为 神经营养蛋白受体。我们还将确定阻止的后果 具有新型 Trk 靶向酪氨酸激酶的 TrkA 与 TrkB 表达肿瘤 抑制剂 CEP-2563。我们的具体目标是： 具体目标 1. 确定 受体结构、信号传导和基因诱导的差异 区分人类中 TrkA 与 TrkB 表达的生物学效应 神经母细胞瘤细胞。 假设：受体结构的根本差异导致 信号传递的差异。立即早期基因诱导和/或相互作用 与P75解释TrkA-和TrkB生物学行为的差异 表达神经母细胞瘤。 具体目标 2. 分析 TrkA 或 TrkB 抑制对 神经母细胞瘤行为和致瘤性。假设：TrkA 的抑制会 诱导细胞凋亡，抑制 TrkB 会减少血管生成， 致瘤性和化疗耐药性。 这些研究的成功完成应该可以解释为什么生物学 表达 TrkA 和 TrkB 的后果是如此不同，以及表达什么部分 受体的变化是造成这种差异的原因。我们还将确定 新型酪氨酸激酶抑制剂 CEP-2563 治疗 TrkA 和 表达 TrkB 的肿瘤。鉴于越来越多的证据表明 Trk 的作用 这些数据认为，各种儿童和成人肿瘤中的受体 强烈支持 Trk 受体抑制在单独或联合治疗中的效用 组合。