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: 8409812
• 负责人: Rani E. George
• 金额: $ 34.13万
• 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/8409812
• 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 Targeting; 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; chemoradiation; 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

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.!

描述（由申请人提供）：尽管在过去的几十年里，治疗方法发生了重大变化，但晚期神经母细胞瘤（一种交感神经系统肿瘤）患儿的长期治愈率仍远不能令人满意。我们最近在原发性神经母细胞瘤中发现了激活ALK受体酪氨酸激酶基因的体细胞突变。研究发现，携带ALK突变的神经母细胞瘤细胞依赖突变的ALK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，当被某些突变激活时，ALK可以维持神经母细胞瘤细胞的生长和存活，从而可以为高风险神经母细胞瘤患者提供一种新的“可药物”靶点。申请人是一名新研究者，将通过解决验证潜在药物靶点、确定次要靶点以增强ALK抑制作用以及开发预防或预防耐药方法的关键问题来验证这一假设。这些研究将采用体外和体内模型。Aim 1测试了ALK突变既可以是乘客也可以是驱动因素的预测，并且只有导致激酶激活的驱动因素才对药物抑制敏感。它还寻求鉴定新的，高选择性的ALK激酶抑制剂，在ALK驱动的神经母细胞瘤细胞中具有有效的活性。Aim 2将寻求初步证据，证明PI3K/PTEN/AKT和RAS/ERK通路是突变ALK触发的主要下游信号通路，联合抑制这些通路和ALK将增强针对神经母细胞瘤细胞的靶向治疗的细胞毒性。Aim 3测试了ALK驱动的NB细胞对ALK激酶抑制剂的抗性是否由于激酶本身的突变或通过篡夺突变ALK通常使用的信号通路诱导抗性的基因的异常激活而出现。该提案的长期目标是通过对alk介导的转化的深入了解，开发出新的治疗方案，可以在高风险神经母细胞瘤儿童的早期试验中进行测试。