Effect of Trk Expression and Inhibition in Neuroblastoma

描述：(申请人提供)神经母细胞瘤是最常见的 儿童中的致命实体肿瘤，但这种肿瘤也有很高的倾向 自发分化经历自发的分化或退化有证据表明 神经营养因子受体Trk家族在肿瘤中发挥重要作用 行为。表达TrkA的神经母细胞瘤在生物学上有利且易发生 自发分化或退化。相比之下，神经母细胞瘤 表达TrkB的基因通常有MYCN扩增，是最常见的 已知的侵袭性和致命性肿瘤。这些肿瘤还表达TrkB配体， 导致了一条自分泌的生存途径。与表达TrkA的肿瘤不同， 暴露于配体可促进在不利条件下的存活，但不会 导致差异化。我们正在探索这种疾病的生物学基础 表达这些高度同源性的神经母细胞瘤的不同行为 神经营养素受体。我们还将确定阻止的后果 TrkA与TrkB通过新型靶向酪氨酸激酶表达肿瘤的比较 抑制剂CEP-2563。我们的具体目标是：具体目标1.确定 受体结构、信号转导和基因诱导的差异 区分TrkA和TrkB在人类中的表达的生物学效应 神经母细胞瘤细胞。 假设：受体结构的根本不同，导致 信号方面的差异。即刻-早期基因诱导和/或相互作用 用P75解释TrkA-和TrkB生物学行为的差异 神经母细胞瘤的表现。 具体目标2.分析TrkA或TrkB抑制对 神经母细胞瘤的行为和致瘤性。假说：抑制TrkA意志 诱导细胞凋亡，抑制TrkB会减少血管生成， 肿瘤致瘤性和对化疗的耐药性。 这些研究的成功完成应该可以解释为什么生物 表达TrkA和TrkB的结果是如此不同， 受体的不同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TrkA的疗效 TrkB表达肿瘤。鉴于越来越多的证据表明Trk的作用 儿童和成人多种肿瘤中的受体，这些数据会争辩说 对于Trk受体抑制在治疗中的应用，单独或在 组合。

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.