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起源于周围神经嵴的肿瘤，是儿童常见的致命性肿瘤。 转录因子MYCN的扩增通常发生在患有高危疾病的儿童中。我们 通过将MYCN转基因的表达引导到神经母细胞瘤的细胞中， 在酪氨酸羟化酶（TH）控制下的基因工程小鼠的外周神经嵴 启动子我们假设： 1). Mycn蛋白在高危MYCN扩增的神经母细胞瘤中起核心作用 2）。靶向Mycn的疗法将在MYCN扩增的神经母细胞瘤中有效。 3）。TH-MYCN转基因和p53缺失的小鼠模型高风险、治疗抗性神经母细胞瘤 复发的患者，并将响应于靶向Mycn的小分子抑制剂。 与提出筛选小分子以识别靶向已知的靶向分子的应用相反， 分子损伤，我们开始与两个有效的和选择性的磷脂酰肌醇-3 '激酶（PI 3 K）抑制剂 现在在临床试验中，似乎非常适合作为治疗神经母细胞瘤和Mycn蛋白。我们将 描述这些药物的作用机制，分析肿瘤细胞与细胞之间的相互作用 构成了微环境。我们将评估Mycn蛋白的不稳定性，以及随后的影响， 对肿瘤负荷和生存率的影响。我们还建议研究和化学修饰Aurora的临床抑制剂 激酶（AURKA）已经在神经母细胞瘤中显示出前景，以建立针对两者的额外活性 Mycn蛋白与耐药神经母细胞瘤。 我们的目标是： 目标1.检测现有临床PI 3 K和PI 3 K/mT 0 R抑制剂对神经母细胞瘤的活性 和Mycn蛋白质。我们假设这些化合物对患有以下疾病的患者有效且安全： MYCN扩增的神经母细胞瘤。 目标2.阐明与PI 3 K抑制剂协同作用的其他靶标和小分子， 降解Mycn。我们假设1）。AurkA的支架依赖性和激酶依赖性功能 在神经母细胞瘤中对这种蛋白质的活性有独立的贡献。2）。DFG输出和a-C输出 抑制剂将破坏这两种功能，并将在神经母细胞瘤中显示功效。