Targeting Oncogenic ALK Signaling in Neuroblastoma

靶向神经母细胞瘤中的致癌 ALK 信号转导

基本信息

批准号：
8462569
负责人：
Yael P Mosse
金额：
$ 31.12万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8462569
关键词：
Anchorage-Independent Growth Biochemical Biological Assay Cell Line Cell Proliferation Cell surface Cells Child Childhood Clinic Clinical Clinical Trials Code Correlation Studies DNA Development Diagnosis Disease Dose Drug Exposure Embryonal Cancers Frequencies Future Gene Mutation Gene Transfer Genes Genetic Predisposition to Disease Genetic Screening Germ-Line Mutation Health Human Immunodeficient Mouse In Vitro Inherited Inhibitory Concentration 50 Lentivirus Vector Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Mediating Modeling Morbidity - disease rate Mutation Neural Crest Neuroblastoma Oncogene Activation Oncogenes Oncogenic Pathogenesis Patients Phase Phenotype Phosphorylation Phosphotransferases Property Protein Tyrosine Kinase Receptor Protein-Tyrosine Kinases Recommendation Role Sampling Signal Pathway Signal Transduction Structure of retinal pigment epithelium Surveys Survival Rate Survivors Testing Therapeutic Tissues Tumorigenicity Tyrosine Kinase Domain Validation Work Xenograft procedure anaplastic lymphoma kinase base cell type chemoradiation chemotherapy cost cytotoxic cytotoxicity design gain of function improved in vivo mortality mutant neuroblastoma cell novel therapeutics overexpression pre-clinical preclinical evaluation prognostic response therapeutic target tool tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Neuroblastoma is an important pediatric cancer as it contributes disproportionately to childhood disease-related morbidity and mortality. We have recently discovered that germline mutations in the anaplastic lymphoma kinase (ALK) gene explain most hereditary neuroblastomas, and that activating mutations can also be somatically acquired. This project will extend our work focused on the overriding hypothesis that ALK is a critical neuroblastoma oncogene and that activation of this cell surface kinase is a tractable therapeutic target. We propose three Specific Aims to validate this hypothesis and extend this work towards new therapeutic strategies in the clinic. First, we will characterize the full spectrum and frequency of germline and somatic DNA alterations (mutation, amplification, translocation) leading to ALK activation using a fully annotated set of 1500 sporadic neuroblastoma tumors obtained at diagnosis, all with available matched germline DNA, and a large set of human neuroblastoma derived cell lines. Second, we will identify the functionally relevant ALK mutations that contribute to the neuroblastoma oncogenic phenotype and examine how these mutations differentially activate downstream signaling pathways. We will determine the malignant transforming properties of all mutations identified in Aim 1 by forcibly over expressing ALK mutants to neural crest-derived retinal pigment epithelial cells (RPE1). To understand the mechanism for malignant transformation, we will survey the downstream signaling pathways activated in ALK mutant and wild-type cells. Finally, we will determine the varying sensitivity of different ALK mutations to pharmacologic inhibition, work that should provide the impetus for developing therapeutic strategies aimed at inhibiting ALK-mediated signaling in the clinic. Preclinical evaluations of anti-tumor efficacy will be designed to quickly develop the rationale necessary to move discoveries in this project to early Phase clinical trials in children with neuroblastoma.

描述（由申请人提供）：神经母细胞瘤是一种重要的儿科癌症，因为它对儿童疾病相关的发病率和死亡率造成不成比例的影响。我们最近发现间变性淋巴瘤激酶（ALK）基因的种系突变可以解释大多数遗传性神经母细胞瘤，并且激活突变也可以通过体细胞获得。该项目将扩展我们的工作重点，即 ALK 是一种关键的神经母细胞瘤癌基因，并且这种细胞表面激酶的激活是一个易于处理的治疗靶点。我们提出了三个具体目标来验证这一假设，并将这项工作扩展到临床新的治疗策略。首先，我们将使用诊断时获得的一组完整注释的 1500 个散发性神经母细胞瘤肿瘤来描述导致 ALK 激活的种系和体细胞 DNA 改变（突变、扩增、易位）的全谱和频率，所有这些肿瘤都具有可用的匹配种系 DNA，以及大量人类神经母细胞瘤衍生细胞系。其次，我们将确定导致神经母细胞瘤致癌表型的功能相关 ALK 突变，并检查这些突变如何差异激活下游信号通路。我们将通过向神经嵴衍生的视网膜色素上皮细胞 (RPE1) 强制过度表达 ALK 突变体来确定目标 1 中确定的所有突变的恶性转化特性。为了了解恶性转化的机制，我们将调查 ALK 突变型和野生型细胞中激活的下游信号通路。最后，我们将确定不同 ALK 突变对药物抑制的不同敏感性，这项工作将为开发旨在抑制临床上 ALK 介导的信号传导的治疗策略提供动力。抗肿瘤功效的临床前评估将旨在快速发展必要的基本原理，将该项目的发现转移到神经母细胞瘤儿童的早期临床试验中。