TARGETING MYCN PROTEIN WITH SMALL MOLECULES

用小分子靶向 MYCN 蛋白

• 批准号: 7897366
• 负责人: WILLIAM A WEISS
• 金额: $ 29.29万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897366
• 关键词: 1-Phosphatidylinositol 3-Kinase; Cells; Chemistry; Child; Clinical; Clinical Trials; Combined Modality Therapy; Disease; Drug resistance; Elements; Genetically Engineered Mouse; Goals; In Vitro; Lesion; MYCN gene; Measures; Mediating; Modeling; Molecular; Mus; Mutation; Neural Crest; Neuroblastoma; Newly Diagnosed; Patients; Pediatric Neoplasm; Peripheral; Phosphotransferases; Play; Pre-Clinical Model; Proteins; Rattus; Relapse; Risk; Role; Safety; Scaffolding Protein; Signal Transduction; Solid Neoplasm; TP53 gene; Testing; Transgenes; Transgenic Mice; Tumor Burden; Tyrosine 3-Monooxygenase; aurora kinase; aurora-A kinase; chemotherapy; combinatorial; high risk; human FRAP1 protein; in vivo; inhibitor/antagonist; insight; kinase inhibitor; mTOR Inhibitor; mutant; neoplastic cell; novel; pre-clinical; promoter; scaffold; small molecule; therapy resistant; transcription factor; tumor

Neuroblastoma, a tumor of peripheral neural crest origin, is a common and lethal tumor of childhood. Amplification of the transcription factor MYCN occurs commonly in children with high-risk disease. We generated a model for high-risk, neuroblastoma by directing expression of a MYCN transgene to the peripheral neural crest of genetically engineered mice, under control of the Tyrosine Hydroxylase (TH) promoter. We hypothesize that: 1).Mycn protein plays a central role In high-risk MYCN-ampllfled neuroblastoma. 2). Therapies targeting Mycn will be effective in MYCN-amplified neuroblastoma. 3). Mice transgenic for TH-MYCN and deleted forp53 model high-risk, therapy-resistant neuroblastoma In relapsed patients, and wilt respond to small molecule Inhibitors targeting Mycn. In contrast to applications that propose to screen small molecules to identify one that targets a known molecular lesion, we are starting with two potent and selective phosphatidylinositol-3'kinase (PI3K) inhibitors now in clinical trials that appear ideally suited as therapy against neuroblastoma and Mycn protein. We will characterize the mechanism of action for these agents, analyzing interactions between tumor cells and cells that comprise the microenvironment. We will assess destabilization of Mycn protein, and subsequent impact on tumor burden and survival. We also propose to study and chemically modify a clinical inhibitor of Aurora kinase (AURKA) that already shows promise in neuroblastoma, to build in additional activity against both Mycn protein and drug resistant neuroblastoma. Our aims are: Aim 1. To test available clinical PI3K and PI3K/mT0R inhibitors for activity against neuroblastoma and Mycn protein. We hypothesize that these compounds will be effective and safe in patients with MYCN-amplified neuroblastoma. Aim 2. To clarify additional targets and small molecules that cooperate with inhibitors of PI3K to degrade Mycn. We hypothesize 1). That scaffold-dependent and kinase dependent functions of AurkA contribute independently to the activity of this protein In neuroblastoma. 2). That DFG-out and a-C out inhibitors will disrupt both functions and will show efficacy In neuroblastoma.

神经母细胞瘤是一种外周神经rest起源的肿瘤，是一种常见且致命的儿童肿瘤。 转录因子MYCN的扩增通常发生在高风险疾病的儿童中。我们 通过将MYCN转基因表达到to中，生成了高风险的神经母细胞瘤模型 酪氨酸羟化酶（Th）的控制，基因工程小鼠的周围神经rest（Th） 发起人。我们假设这一点： 1）.MyCN蛋白在高危MyCN-Ampllflled神经母细胞瘤中起着核心作用。 2）。靶向MYCN的疗法将有效在MyCN扩增的神经母细胞瘤中。 3）。小鼠用于TH-MYCN的转基因和删除的Forp53模型高风险，耐治疗的神经母细胞瘤 复发患者，枯萎对针对MYCN的小分子抑制剂反应。 与提议筛选小分子以识别针对已知的一个靶向的应用相反 分子病变，我们是从两个有效和选择性磷脂酰肌醇-3'kinase（pI3K）抑制剂开始的 现在，在临床试验中，似乎非常适合针对神经母细胞瘤和MYCN蛋白的治疗。我们将 表征这些药物的作用机理，分析肿瘤细胞与细胞之间的相互作用 这包括微环境。我们将评估MYCN蛋白质的不稳定，并随后影响 在肿瘤负担和生存下。我们还建议研究和化学修改Aurora的临床抑制剂 激酶（Aurka）已经在神经母细胞瘤中显示出有望 MYCN蛋白和耐药性神经母细胞瘤。 我们的目标是： 目的1。测试可用的临床PI3K和PI3K/MT0R抑制剂，以实现对神经母细胞瘤的活性 和mycn蛋白。我们假设这些化合物对患者有效且安全 MyCN扩增的神经母细胞瘤。 目标2。阐明与PI3K抑制剂合作的其他靶标和小分子 降级mycn。我们假设1）。 Aurka的脚手架依赖性和激酶依赖性功能 独立于该蛋白在神经母细胞瘤中的活性。 2）。那个DFG淘汰和A-C 抑制剂将破坏这两个功能，并将显示神经母细胞瘤的功效。