Targeting Oncogenic ALK Signaling in Neuroblastoma

靶向神经母细胞瘤中的致癌 ALK 信号转导

• 批准号: 7694503
• 负责人: Yael P Mosse
• 金额: $ 34.4万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7694503
• 关键词: Anchorage-Independent Growth; Biochemical; Biological Assay; Cell Line; Cell Proliferation; Cell surface; Cells; Child; Childhood; Classification; 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; chemotherapy; cost; cytotoxic; cytotoxicity; design; gain of function; improved; in vivo; mortality; mutant; novel therapeutics; overexpression; pre-clinical; preclinical evaluation; prognostic; public health relevance; response; therapeutic target; tool; tumor; tumorigenesis

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. PUBLIC HEALTH RELEVANCE: Neuroblastoma remains a challenging childhood health problem as our attempts to cure more patients has resulted in only very modest improvements in cure rates, but with the associated cost of extensive morbidity in survivors. Our work discovering the genetic etiology of human neuroblastoma provides the first evidence for oncogenic activation of ALK via mutation of the kinase domain. This project will result in important steps forward in developing rational therapeutic strategies aimed at inhibiting ALK- mediated signaling for this often-devastating childhood cancer.

描述（由申请人提供）：神经母细胞瘤是一种重要的儿童癌症，因为它对儿童疾病相关的发病率和死亡率有不成比例的贡献。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，激活这种细胞表面激酶是一种可处理的治疗靶点。我们提出三个具体目标来验证这一假设，并将这项工作扩展到临床的新治疗策略。首先，我们将利用在诊断时获得的1500例散发性神经母细胞瘤肿瘤的完整注释集来描述导致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的种系DNA，以及一大批人类神经母细胞瘤衍生细胞系。其次，我们将确定与神经母细胞瘤致癌表型有关的功能相关的ALK突变，并研究这些突变如何以不同的方式激活下游信号通路。我们将通过向神经嵴源性视网膜色素上皮细胞（RPE1）强行过表达ALK突变体来确定Aim 1中鉴定的所有突变的恶性转化特性。为了了解恶性转化的机制，我们将研究在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ALK介导的信号传导的临床治疗策略提供动力。抗肿瘤疗效的临床前评估将被设计为快速发展必要的理论基础，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。公共卫生相关性：神经母细胞瘤仍然是一个具有挑战性的儿童健康问题，因为我们试图治愈更多的患者，但治愈率只有非常有限的提高，而幸存者的发病率却很高。我们的工作发现了人类神经母细胞瘤的遗传病因，为ALK通过激酶结构域的突变致癌激活提供了第一个证据。该项目将在开发合理的治疗策略方面取得重要进展，旨在抑制ALK介导的信号传导，治疗这种经常毁灭性的儿童癌症。