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

• 批准号: 8040502
• 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
• 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/8040502
• 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; research study; resistance mechanism; small molecule; therapeutic target; tumor; uncontrolled cell growth

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(申请人提供)：尽管在过去几十年中治疗方法有了重大改进，但儿童晚期神经母细胞瘤(一种交感神经系统肿瘤)的长期治愈率仍远未令人满意。我们最近在原发神经母细胞瘤中发现了ALK受体酪氨酸激酶基因的激活体细胞突变。携带ALK突变的神经母细胞瘤细胞被发现依赖突变的ALK生存，并且对小分子化合物的抑制非常敏感。这一提议的中心假设是，当ALK被某些突变激活时，可以维持神经母细胞瘤细胞的生长和存活，从而可能为高危神经母细胞瘤患者提供一个新的可用药的靶点。申请者是一名新的研究人员，他将通过解决关键问题来验证这一假设，这些关键问题对于确认潜在的药物靶点、识别辅助靶点以增强ALK抑制的效果以及开发预防或预防耐药性的方法至关重要。体外和体内模型都将被用于这些研究。AIM 1测试了这样的预测，即ALK突变可能是乘客，也可能是司机，只有导致激酶激活的司机才会对药物抑制敏感。它还寻求寻找在ALK驱动的神经母细胞瘤细胞中具有强大活性的新的、高选择性的ALK激酶抑制剂。目的2将寻求初步证据表明，PI3K/PTEN/AKT和RAS/ERK通路是突变的ALK触发的主要下游信号通路，抑制这些通路与ALK一起，将增强针对神经母细胞瘤细胞的靶向治疗的细胞毒作用。目的3检测ALK驱动的NB细胞对ALK激酶抑制剂的耐药性是否是由于ALK本身的突变或通过篡改突变的ALK通常采用的信号通路而导致的基因异常激活而导致的。这项提议的长期目标是根据对ALK介导的转化的见解开发新的治疗方案，这些方案可以在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肿瘤，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中发现了酪氨酸激酶受体ALK的关键突变，这为靶向治疗提供了一个新的焦点。该提案旨在进一步确定这些突变的特征，测试针对ALK及其下游信号通路的抑制剂化合物，并破译ALK抑制剂的耐药机制，最终目标是开发可能改善患有这种毁灭性疾病的儿童的生存的药物。