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: 8598861
• 负责人: Rani E. George
• 金额: $ 35.22万
• 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/8598861
• 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 Extracranial Solid Tumor; 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）：尽管过去几十年来治疗方法发生了重大变化，但患有晚期神经母细胞瘤（一种交感神经系统肿瘤）的儿童的长期治愈率仍然远未令人满意。我们最近发现原发性神经母细胞瘤中 ALK 受体酪氨酸激酶基因的体细胞突变被激活。研究发现，携带 ALK 突变的神经母细胞瘤细胞的生存依赖于突变型 ALK，并且对小分子化合物的抑制极其敏感。该提案的中心假设是，ALK 在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，因此可以为高危神经母细胞瘤患者提供新的“可成药”靶点。作为一名新研究者，申请人将通过解决对验证潜在药物靶点、确定次要靶点以增强 ALK 抑制作用以及开发预防或阻止耐药性的方法至关重要的关键问题来检验这一假设。这些研究将使用体外和体内模型。目标 1 测试了以下预测：ALK 突变可以是乘客，也可以是驱动因素，并且只有导致激酶激活的驱动因素才会对药物抑制敏感。它还寻求鉴定对 ALK 驱动的神经母细胞瘤细胞具有有效活性的新型、高选择性 ALK 激酶抑制剂。目标 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，并且这些通路与 ALK 的联合抑制将增强靶向治疗的细胞毒性。至神经母细胞瘤细胞。目标 3 测试 ALK 驱动的 NB 细胞中是否出现对 ALK 激酶抑制剂的耐药性，原因是激酶本身的突变或基因的异常激活，通过篡夺突变 ALK 通常使用的信号通路来诱导耐药性。该提案的长期目标是通过深入了解 ALK 介导的转化来开发新的治疗方案，并可在患有高危神经母细胞瘤的儿童中进行早期试验。