The ALK receptor tyrosine kinase as a therapeutic target in neuroblastoma

ALK 受体酪氨酸激酶作为神经母细胞瘤的治疗靶点

基本信息

批准号：
8206709
负责人：
Rani E. George
金额：
$ 36.31万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8206709
关键词：
4 year old ALK gene Address Age Alleles Apoptosis Biology Cancer Biology Cancer Etiology Cell Cycle Arrest Cell Line Cells Cessation of life Child Childhood Solid Neoplasm Chronic Clinical Combined Modality Therapy Dana-Farber Cancer Institute Disease Drug Delivery Systems Drug resistance Exhibits Foundations Gatekeeping Gene Activation Goals Gray unit of radiation dose Growth In Vitro Interleukin-3 Laboratories Lead MAPK3 gene MYCN gene Malignant Neoplasms Mediating Mediator of activation protein Methods Modeling Modification Mutation Neural Crest Neuroblastoma Oncogenes Oncogenic Operative Surgical Procedures PTEN gene Pathway interactions Patients Peripheral Pharmaceutical Preparations Phase Phosphorylation Phosphotransferases Positioning Attribute Proto-Oncogene Proteins c-akt Receptor Protein-Tyrosine Kinases Receptor Tyrosine Kinase Gene Reporting Research Personnel Resistance STAT3 gene Signal Pathway Signal Transduction Solid Neoplasm Somatic Mutation Source Staging Stem cells Sympathetic Nervous System Testing Therapeutic Triazoles Urea anaplastic lymphoma kinase clinical application cytokine cytotoxicity diaminopyrimidine expectation high risk improved in vivo Model inhibitor/antagonist insight kinase inhibitor mutant neuroblastoma cell novel novel therapeutics outcome forecast prevent programs public health relevance research study resistance mechanism small molecule therapeutic target tumor uncontrolled cell growth

项目摘要

DESCRIPTION (provided by applicant): Despite major modifications in therapy over the last few decades, the long-term cure rate in children with advanced neuroblastoma, a tumor of the sympathetic nervous system, is still far from satisfactory. We recently discovered activating somatic mutations in the ALK receptor tyrosine kinase gene in primary neuroblastomas. Neuroblastoma cells harboring ALK mutations were found to be dependent on mutant ALK for their survival and were exquisitely sensitive to inhibition by small molecule compounds. The central hypothesis of this proposal is that ALK, when activated by certain mutations, can sustain the growth and survival of neuroblastoma cells and thus could provide a novel "druggable" target in patients with high-risk neuroblastoma. The applicant, who is a New Investigator, will test this hypothesis by addressing key issues that are fundamental to validating a potential drug target, to identifying secondary targets to enhance the effects of ALK inhibition, and to developing methods to prevent or forestall drug resistance. Both in vitro and in vivo models will be utilized in these studies. Aim 1 tests the prediction that ALK mutations can be either passengers or drivers and that only drivers leading to kinase activation will be sensitive to pharmacological inhibition. It also seeks to identify novel, highly selective ALK kinase inhibitors with potent activity in ALK-driven neuroblastoma cells. Aim 2 will pursue preliminary evidence that the PI3K/PTEN/AKT and the RAS/ERK pathways serve as the principal downstream signaling pathways triggered by mutant ALK and that combined inhibition of these pathways, together with ALK, would enhance the cytotoxicity of targeted therapy directed to neuroblastoma cells. Aim 3 tests whether resistance to ALK kinase inhibitors emerges in ALK-driven NB cells because of mutations within the kinase itself or aberrant activation of genes that induce resistance by usurping the signaling pathways normally employed by mutant ALK. The long-term goal of this proposal is to develop novel therapeutic options from insights into ALK-mediated transformation that can be tested in early phase trials in children with high-risk neuroblastoma.! PUBLIC HEALTH RELEVANCE: Neuroblastoma is the most common extracranial solid tumor of children, and the leading cause of cancer deaths in children 1-4 years of age. We have recently discovered critical mutations in the tyrosine kinase receptor, ALK, in neuroblastoma tumors that provide a novel focus for targeted therapy. This proposal seeks to further characterize these mutations, to test inhibitor compounds directed against ALK and its downstream signaling pathways, and to decipher the mechanisms of resistance to ALK inhibitors with the ultimate goal of developing drugs that may improve the survival of children with this devastating disease.

描述（由申请人提供）：尽管过去几十年来治疗进行了重大修改，但晚期神经母细胞瘤儿童的长期治愈率（交感神经系统的肿瘤）仍然远非令人满意。我们最近在原代神经母细胞瘤中发现了ALK受体酪氨酸激酶基因中的体细胞突变。发现携带ALK突变的神经母细胞瘤细胞依赖于突变碱的存活，并且对小分子化合物的抑制非常敏感。该提议的中心假设是，当通过某些突变激活时，ALK可以维持神经母细胞瘤细胞的生长和存活，因此可以为具有高危神经母细胞瘤的患者提供一种新型的“可药物”靶标。申请人是一名新研究者，将通过解决验证潜在药物靶基础的关键问题来检验这一假设，以确定次要靶标，以增强ALK抑制的影响，并开发预防或防止耐药性的方法。这些研究都将在体外和体内模型中使用。 AIM 1测试ALK突变可以是乘客或驱动因素，并且只有导致激酶激活的驱动因素才能对药理抑制敏感。它还试图鉴定具有碱性神经母细胞瘤细胞有效活性的新型，高度选择性的ALK激酶抑制剂。 AIM 2将寻求初步证据表明，PI3K/PTEN/AKT和RAS/ERK途径是由突变ALK触发的主要下游信号通路，并且将这些途径抑制与ALK结合在一起，将增强对靶向治疗的靶向治疗的靶向治疗。 AIM 3测试是由于激酶本身内的突变还是异常的基因激活，该基因的耐药性是在ALK驱动的NB细胞中出现的，或通过篡夺通常由突变Alk使用的信号传导途径诱导抗性的基因激活。该提案的长期目标是开发新的治疗选择，从洞察力到ALK介导的转化，可以在具有高危神经母细胞瘤儿童的早期试验中进行测试。公共卫生相关性：神经母细胞瘤是儿童最常见的颅外实体瘤，也是1-4岁儿童癌症死亡的主要原因。我们最近在神经母细胞瘤肿瘤中发现了酪氨酸激酶受体ALK中的临界突变，这些突变为靶向治疗提供了一种新颖的重点。该提案旨在进一步表征这些突变，测试针对ALK及其下游信号通路的抑制剂化合物，并破译对碱抑制剂的耐药机制，其最终目的是开发药物，这些药物可能会改善这种破坏性疾病的儿童生存。