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的， 儿童致命的实体瘤，但该肿瘤的倾向也很高 经历自发分化或回归。有证据表明这一点 神经营养蛋白受体的TRK家族在肿瘤中起着至关重要的作用 行为。表达TRKA的神经母细胞瘤在生物学上有利且容易发生 自发分化或回归。相反，神经母细胞瘤 表达TRKB通常具有MYCN扩增，并且是最多的 侵略性和致命的肿瘤已知。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， 暴露于配体在不利条件下促进生存，但没有 引起分化。我们正在探索生物学基础 表达这些高度同源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 TRKA与TRKB用小说，靶向TRK的酪氨酸激酶表达肿瘤 抑制剂CEP-2563。我们的具体目的是：特定目标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：受体结构的基本差异，导致 信号传导的差异。直接诱导基因诱导和/或相互作用 用p75解释了TRKA和TRKB生物学行为的差异 表达神经母细胞瘤。 具体目的2。分析TRKA或TRKB抑制对 神经母细胞瘤的行为和肿瘤性。假设：TRKA的抑制作用将 诱导凋亡，抑制TRKB将减少血管生成， 肿瘤性和对化学疗法的抗性。 这些研究的成功完成应解释为什么生物学 表达TRKA与TRKB的后果是如此不同，哪一部分 受体的差异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在治疗TRKA和 TRKB表达肿瘤。鉴于越来越多的TRK作用的证据 这些数据会说明各种儿科和成人肿瘤的受体 强烈地单独或在治疗中抑制TRK受体的效用 组合。