Murine Neuroblastoma Models for Preclinical Therapeutics

用于临床前治疗的小鼠神经母细胞瘤模型

基本信息

批准号：
8396359
负责人：
WILLIAM A WEISS
金额：
$ 25.8万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8396359
关键词：
Affect Apoptosis Automobile Driving Biological Assay Blood Vessels Cell Line Cells Child Clinical Clinical Trials Combined Modality Therapy Cytostatics Data Development Developmental Therapeutics Program Disease Disease remission Drug resistance Epigenetic Process Genetic Grant Housing Human In Vitro MAP Kinase Gene MEKs MYCN gene Maintenance Medicine Minority Modeling Molecular Abnormality Monitor Mouse Cell Line Mus Mutant Strains Mice Mutation N-Myc Protein Neural Crest Neuroblastoma PTEN gene Pathway interactions Patients Pediatric Neoplasm Peripheral Phosphotransferases Play Pre-Clinical Model Proteins Relapse Role Signal Transduction Testing Therapeutic Transgenes Transgenic Mice Transgenic Organisms Xenograft procedure autocrine base cytotoxicity feeding high risk improved in vivo inhibitor/antagonist mTOR Inhibitor mouse model mutant neoplastic cell paracrine pre-clinical response tumor

项目摘要

DESCRIPTION (provided by applicant): Neuroblastoma is a common and lethal tumor of childhood. Amplification of MYCN occurs commonly in high-risk disease. We generated a model for primary neuroblastoma by directing expression of a MYCN transgene to the murine peripheral neural crest. Over the past 4y, we validated and established mice transgenic for TH-MYCN as a platform for developmental therapeutics, demonstrating that MYCN protein plays a central role in neuroblastoma, that signaling through PI3K critically stabilizes MYCN, that clinica inhibitors of PI3K destabilize MYCN and improve survival in mice transgenic for TH-MYCN, and that a clinical PI3K inhibitor drives degradation of Mycn cells in-vivo, with secondary paracrine vascular blockade. Our observations, that PI3K signaling stabilizes Mycn protein and that Mycn in tumor cells contributes prominently to the tumor microenvironment, raise new questions. In a tumor with few prominent kinases, how is PI3K activated? How do activation of ALK and loss of NF1 (which contribute to progression in neuroblastoma) influence response to PI3K inhibition? Can we identify translatable combination therapies that promote durable responses? How do these therapies affect the tumor microenvironment? In this application, we will evaluate candidate MYCN-driven miRNAs as activators of PI3K in neuroblastoma. We will generate TH-MYCN mice mutant at Nf1 or Alk, and determine how these genetic abnormalities influence response to PI3K/mTOR inhibitors. We will also identify targeted therapies that cooperate with inhibition of PI3K to induce cytotoxicity, a translatable approach to promote durable responses. The specific aims of this application are: Aim1. To evaluate miR-8208;17-8208;92 as a Mycn target that blocks PTEN, activates PI3K, promoting an autocrine loop which subsequently stabilizes MYCN in neuroblastoma. Aim 2. To evaluate how loss of NF1 and activation of ALK influence response to PI3K/mTOR inhibitors in MYCN-driven neuroblastoma, Aim 3. To identify combination therapies which cooperate with inhibitors of PI3K to drive apoptosis resulting in durable remissions in neuroblastoma. Successful completion of this proposal establishes a mechanistic basis for PI3K activation in neuroblastoma, and identifies new miR targets for therapy, extends the utility of mice transgenic for TH-MYCN, adds new GEM mouse models as platforms for personalized medicine in neuroblastoma, and provides a preclinical rationale to test effective combination therapies in clinical trials, in children with neuroblastoma.

描述（由申请人提供）：神经母细胞瘤是儿童期的常见和致命的肿瘤。 MYCN的扩增通常发生在高危疾病中。我们通过将MYCN转基因表达到鼠外周神经rest中，生成了原发性神经母细胞瘤的模型。 Over the past 4y, we validated and established mice transgenic for TH-MYCN as a platform for developmental therapeutics, demonstrating that MYCN protein plays a central role in neuroblastoma, that signaling through PI3K critically stabilizes MYCN, that clinica inhibitors of PI3K destabilize MYCN and improve survival in mice transgenic for TH-MYCN, and that a clinical PI3K抑制剂在体内驱动MYCN细胞的降解，并带有继发性旁分泌血管阻断。我们的观察结果是，PI3K信号传导稳定了MYCN蛋白，并且肿瘤细胞中的MYCN对肿瘤微环境产生了重要贡献，这引发了新问题。在几乎没有突出激酶的肿瘤中，PI3K如何激活？ ALK的激活和NF1的丧失（有助于神经母细胞瘤的进展）如何影响对PI3K抑制的反应？我们可以确定可促进持久反应的可翻译组合疗法吗？这些疗法如何影响肿瘤微环境？在此应用中，我们将评估候选MYCN驱动的miRNA作为神经母细胞瘤中PI3K的激活剂。我们将在NF1或ALK上产生TH-MYCN小鼠突变体，并确定这些遗传异常如何影响对PI3K/MTOR抑制剂的反应。我们还将确定与抑制PI3K合作以诱导细胞毒性的靶向疗法，这是一种可翻译的方法，可促进持久反应。该应用程序的具体目的是：AIM1。评估miR-8208; 17-8208; 92作为阻断PTEN的MYCN目标，激活PI3K，促进自分泌环，后来稳定了神经母细胞瘤中的MYCN。目的2。要评估NF1的损失和ALK的激活如何影响MYCN驱动的神经母细胞瘤中对PI3K/MTOR抑制剂的反应，目的3。识别与PI3K抑制剂合作的组合疗法，以驱动神经脂母细胞中持久缓解的凋亡。该提案的成功完成为神经母细胞瘤中PI3K激活的机械基础建立了机械基础，并确定了新的miR靶标的用于治疗，扩展了小鼠转基因对Th-Mycn的实用性，将新的GEM鼠标模型作为神经细胞瘤的个性化医学平台，在神经母细胞瘤中的个性化医学，并为有效的NEBIANIAL COMBINALE COMBINATE CHILCATIS提供了临床临床研究，并在临床上提供了临床。