Trk Expression and Inhibition in Human Neuroblastomas

人神经母细胞瘤中 Trk 的表达和抑制

• 批准号: 7760643
• 负责人: GARRETT M BRODEUR
• 金额: $ 38.73万
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760643
• 关键词: Adult; Animal Model; Behavior; Biological; Biological Process; Biotechnology; Brain-Derived Neurotrophic Factor; Breast; Cell Line; Cell Survival; Cells; Child; Childhood; Clinical; Clinical Trials; Critical Pathways; Cytotoxic agent; Data; Differentiation and Growth; Dose; Engineering; Exposure to; Family; Future; Gene Expression; Gene Family; Human; In Vitro; Lead; Ligand Binding; Ligands; MAP Kinase Gene; MYCN gene; Malignant Childhood Neoplasm; Mus; Mutation; Nephroblastoma; Nerve Growth Factor Receptors; Neuroblastoma; Neurotrophic Tyrosine Kinase Receptor Type 2; Outcome; PI3K/AKT; Pathway interactions; Patients; Pattern; Phosphorylation; Phosphorylation Site; Play; Predictive Value; Prostate; Proteins; Relapse; Risk; Role; Sampling; Schedule; Signal Pathway; Signal Transduction; Solid Neoplasm; Structure; Therapeutic Index; Transgenic Mice; Tumorigenicity; Tyrosine Kinase Inhibitor; Xenograft procedure; autocrine; behavior test; deletion analysis; gene induction; high risk; human FRAP1 protein; in vivo; inhibitor/antagonist; insight; medulloblastoma; novel; paracrine; patient population; protein structure; public health relevance; receptor; receptor expression; receptor structure function; response; tumor; Adult; Animal Model; Behavior; Biological; Biological Process; Biotechnology; Brain-Derived Neurotrophic Factor; Breast; Cell Line; Cell Survival; Cells; Child; Childhood; Clinical; Clinical Trials; Critical Pathways; Cytotoxic agent; Data; Differentiation and Growth; Dose; Engineering; Exposure to; Family; Future; Gene Expression; Gene Family; Human; In Vitro; Lead; Ligand Binding; Ligands; MAP Kinase Gene; MYCN gene; Malignant Childhood Neoplasm; Mus; Mutation; Nephroblastoma; Nerve Growth Factor Receptors; Neuroblastoma; Neurotrophic Tyrosine Kinase Receptor Type 2; Outcome; PI3K/AKT; Pathway interactions; Patients; Pattern; Phosphorylation; Phosphorylation Site; Play; Predictive Value; Prostate; Proteins; Relapse; Risk; Role; Sampling; Schedule; Signal Pathway; Signal Transduction; Solid Neoplasm; Structure; Therapeutic Index; Transgenic Mice; Tumorigenicity; Tyrosine Kinase Inhibitor; Xenograft procedure; autocrine; behavior test; deletion analysis; gene induction; high risk; human FRAP1 protein; in vivo; inhibitor/antagonist; insight; medulloblastoma; novel; paracrine; patient population; protein structure; public health relevance; receptor; receptor expression; receptor structure function; response; tumor

DESCRIPTION (provided by applicant): Neuroblastoma (NB) is a common and deadly solid tumor in children that displays heterogeneous clinical behavior, from spontaneous regression to relentless progression. Evidence suggests that the TRK family of neurotrophin receptors plays a critical role in this behavior. NBs expressing TrkA are biologically favorable and prone to spontaneous regression or differentiation, whereas, TrkB-expressing tumors are extremely aggressive and often fatal tumors. We hypothesize that structural differences between TrkA and TrkB lead to differences in signaling and gene induction that result in these very different clinical behaviors. Furthermore, Trk inhibition will be an effective adjunct to treating these tumors, with a wide therapeutic index. Aim 1: We will determine the unique features of receptor structure that result in differences in protein association or signaling, which in turn cause the different biological effects of TrkA vs. TrkB activation in human NBs. We plan to examine differences between TrkA and TrkB protein associations in response to ligand binding that may lead to differences in the signaling pathways or duration of signaling; use mutation or deletion analysis to confirm the receptor domain(s) responsible for these different biological responses; and analyze gene expression patterns induced by ligand activation of TrkA or TrkB to identify critical pathways that contribute to favorable and unfavorable behaviors, respectively. Aim 2: We will compare currently available and novel Trk inhibitors to identify the optimum agent for incorporation into clinical trials. We plan to: treat TrkA and TrkB expressing NB cells in vitro and in vivo with Trk-specific tyrosine kinase inhibitors from several biotechnology companies to determine the effects on cell survival, growth, differentiation and tumorigenicity; treat Trk-expressing NBs in vitro and in vivo with novel Trk inhibitors in combination with conventional cytotoxic agents to determine optimum combinations, dose and schedule; and treat NBs in vitro and in animal models with Trk inhibitors combined with selective downstream inhibitors of PI3K/AKT, RAS, MAPK, or mTOR to determine if the combination has a greater antitumor effect than either agent alone. Aim 3: We will determine the pattern of expression of Trk family genes in primary NBs, and determine the clinical consequences of this expression. We plan to screen 805 representative primary NBs for the pattern of Trk family gene expression, and determine the predictive value of this expression pattern in selected patient subsets. We will also use this information to identify relapsed patients who would be candidates for Trk-targeted therapy. The successful completion of these studies will clarify structural differences in TrkA or TrkB that lead to differences in biological function and clinical behavior. We will determine the efficacy of Trk inhibitor therapy, alone or combined with other agents, on NBs in animal models. Finally, we will determine the pattern of Trk expression in primary NBs to predict outcome and to identify candidates for Trk inhibitor therapy. Trk receptors are expressed in other pediatric and adult tumors, so these studies will have broader implications for them as well. PUBLIC HEALTH RELEVANCE: Neuroblastoma is a common and lethal childhood cancer, and we need novel therapies that are more effective and less toxic. Our studies will provide valuable insight into the important role of the TrkA and TrkB receptors in regulating clinical behavior. We will also determine the optimum Trk inhibitor (agent, dose, schedule) to incorporate into future clinical trials, and we will determine which tumors express Trk receptors to identify who would benefit from Trk inhibitor therapy.

描述（由申请人提供）：神经母细胞瘤（NB）是儿童的常见且致命的实体瘤，显示出异质临床行为，从自发回归到无情的进展。证据表明，神经营养蛋白受体的TRK家族在这种行为中起着至关重要的作用。表达TRKA的NB在生物学上有利，容易自发回归或分化，而表达TRKB的肿瘤非常侵略性且通常是致命的肿瘤。我们假设TRKA和TRKB之间的结构差异会导致信号传导和基因诱导的差异，从而导致这些截然不同的临床行为。此外，TRK抑制作用将是通过广泛的治疗指数治疗这些肿瘤的有效辅助。 AIM 1：我们将确定受体结构的独特特征，从而导致蛋白质关联或信号传导差异，这又导致人类NBS中TRKA与TRKB激活的生物学效应不同。我们计划检查TRKA和TRKB蛋白关联之间对配体结合的差异，这可能导致信号通路或信号持续时间的差异；使用突变或缺失分析来确认负责这些不同生物学反应的受体结构；并分析由TRKA或TRKB的配体激活诱导的基因表达模式，以识别分别有助于有利和不利行为的关键途径。 AIM 2：我们将比较当前可用的和新颖的TRK抑制剂，以识别掺入临床试验中的最佳药物。我们计划：从几个生物技术公司中用TRK特异性酪氨酸激酶抑制剂在体外和体内处理TRKA和TRKB，以确定对细胞存活，生长，分化和肿瘤性的影响；与常规细胞毒性剂结合使用新型TRK抑制剂，在体外和体内处理TRK的NBS，以确定最佳组合，剂量和时间表；并用TRK抑制剂在体外和动物模型中处理NBS，并结合了PI3K/AKT，RAS，MAPK或MTOR的选择性下游抑制剂，以确定该组合是否比单独使用任何药物具有更大的抗肿瘤效应。 AIM 3：我们将确定原代NBS中TRK家族基因表达的模式，并确定该表达的临床后果。我们计划筛选805代表性的主要NB，以进行TRK家族基因表达的模式，并确定该表达模式在选定的患者子集中的预测值。我们还将使用这些信息来识别将成为TRK靶向治疗的候选者的复发患者。这些研究的成功完成将阐明TRKA或TRKB的结构差异，从而导致生物学功能和临床行为的差异。我们将单独确定TRK抑制剂疗法的功效，或与其他药物在动物模型中的NBS上的疗效。最后，我们将确定主要NBS中TRK表达的模式，以预测结果并确定TRK抑制剂治疗的候选者。 TRK受体在其他儿科和成人肿瘤中表达，因此这些研究也将对它们产生更广泛的影响。公共卫生相关性：神经母细胞瘤是一种常见且致命的儿童癌症，我们需要更有效且毒性较小的新型疗法。我们的研究将为TRKA和TRKB受体在调节临床行为中的重要作用提供宝贵的见解。我们还将确定最佳的TRK抑制剂（代理，剂量，时间表）以纳入未来的临床试验，我们将确定哪些肿瘤表达TRK受体，以确定谁将受益于TRK抑制剂治疗。