TARGETING MYCN PROTEIN WITH SMALL MOLECULES

神经母细胞瘤是一种起源于周围神经脊区的肿瘤，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 酪氨酸羟基酶(TH)调控下的基因工程小鼠外周神经突起 推动者。我们假设： 1)Mycn蛋白在MYCN扩增的高危神经母细胞瘤中起中心作用。 2)。针对Mycn的治疗将对MYCN扩增的神经母细胞瘤有效。 3)。转基因TH-MYCN和缺失p53的小鼠模型高危耐药神经母细胞瘤 复发患者，WILT对靶向Mycn的小分子抑制剂有反应。 与提出筛选小分子以识别以已知的 分子损伤，我们从两种有效和选择性的磷脂酰肌醇-3‘激酶(PI3K)抑制剂开始 现在正在进行临床试验，这似乎是治疗神经母细胞瘤和Mycn蛋白的理想选择。我们会 描述这些药物的作用机制，分析肿瘤细胞和细胞之间的相互作用 它们构成了微环境。我们将评估Mycn蛋白的不稳定及其后续影响 肿瘤负担和存活率。我们还建议研究和化学修饰一种临床上使用的Aurora抑制剂 已经在神经母细胞瘤中显示出希望的激酶(AURKA)，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： 目的1.检测临床可用的PI3K和PI3K/mT0R抑制剂对神经母细胞瘤的抑制作用 和Mycn蛋白。我们推测，这些化合物对慢性阻塞性肺疾病患者是有效和安全的。 MYCN扩增的神经母细胞瘤。 目的2.阐明与PI3K抑制剂协同作用的其他靶点和小分子 降级Mycn。我们假设1)。AurkA的支架依赖和激酶依赖功能 在神经母细胞瘤中对这种蛋白的活性有独立的贡献。2)。DFG-Out和A-C Out 抑制剂将扰乱这两种功能，并将在神经母细胞瘤中显示出疗效。

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.