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.

神经母细胞瘤起源于周围神经嵴，是儿童常见的致死性肿瘤。