Targeting Oncogenic ALK Signaling in Neuroblastoma

靶向神经母细胞瘤中的致癌 ALK 信号转导

基本信息

批准号：
9271153
负责人：
Yael P Mosse
金额：
$ 37.43万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9271153
关键词：
Address Adverse effects Alpha Cell Automobile Driving Biochemical Biological Assay Biological Markers Cancer Burden Cells Child Childhood Chimeric Proteins Clinic Clinical Clinical Trials Combined Modality Therapy Computer Simulation DNA Sequence Alteration Data Development Diagnosis Disease Drug Interactions Drug resistance Embryo Evaluation Event FDA approved Genes Genetic Genetic Predisposition to Disease Genome Goals Histologic Inherited Lead Left Life Ligands Lymphoma Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Mediating Mediator of activation protein Mission Modeling Molecular Abnormality Molecular Target Morbidity - disease rate Motivation Mutate Mutation Nature Neonatal Nervous system structure Neuroblastoma Newly Diagnosed Oncogenes Oncogenic Outcome Pathway interactions Patients Pharmacology Phase Phase I Clinical Trials Phase II Clinical Trials Phosphotransferases Positioning Attribute Preclinical Testing Process Protein Tyrosine Kinase Public Health Receptor Protein-Tyrosine Kinases Refractory Relapse Research Research Project Grants Research Proposals Resistance Route Signal Pathway Signal Transduction Stratification Survival Rate Testing Therapeutic Treatment Protocols United States National Institutes of Health Variant Vertebral column Work actionable mutation anaplastic lymphoma kinase base biochemical model childhood cancer mortality clinical biomarkers combinatorial crizotinib design drug mechanism drug sensitivity evidence base gain of function mutation genomic profiles high risk improved improved outcome inhibitor/antagonist kinase inhibitor mutant neoplastic cell neuroblastoma cell next generation novel novel therapeutics pre-clinical prediction algorithm public health relevance research clinical testing resistance mechanism response response biomarker small molecule targeted treatment therapy resistant treatment response treatment strategy tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Neuroblastoma (NB) remains a leading cause of childhood cancer deaths. Children who do survive are left with long-term side effects, many of which can be life threatening. In this era of more rational therapies, substantial efforts are bein made to identify optimal targets. We discovered that activating mutations of the ALK oncogene are the major cause of hereditary NB, and that somatically acquired mutations and amplification events often drive the malignant process in a subset of sporadic tumors. This was the motivation for the first phase of this project, where we then demonstrated that the common ALK mutations result in differential kinase activation and differential sensitivity to ATP-competitive inhibitors. This work established ALK as a tractable molecular target in NB and led to a now completed pediatric phase 1 trial and ongoing phase 2 trial of crizotinib, the only FDA approved ALK inhibitor. The results from the first 4 years of our R01 show the complexity of ALK activation in NB, and demonstrate that inhibition of a mutant kinase domain is much more challenging than fusion proteins present in lymphomas and lung cancer. This provides the impetus for the long-term goal of this research proposal to develop novel therapeutic strategies aimed at effectively inhibiting ALK-mediated signaling. The primary objective is to develop a responder hypothesis for therapeutic stratification of newly diagnosed patients with ALK-mutant NB, to elucidate mechanisms of resistance to crizotinib, and to define circumvention strategies in the clinic. The central hypothesis to be explored here is that rational and effective ALK-inhibition strategies can only be successfully developed after elucidation of the clinical implications of ALK alterations identified in patients and the mechanisms driving intrinsic resistance. The motivation is the urgent need to improve high-risk NB survival rates and decrease treatment-related morbidities. We will test our central hypothesis in three specific aims: 1) Define the functional consequences of patient-derived ALK alterations; 2) Identify mechanisms of sensitivity and resistance to ALK inhibition; and 3) Develop rational therapeutic combinations targeting ALK signaling pathways to overcome resistance. The first Aim, based on recent unpublished data showing a variety of alternative genetic mechanisms for ALK activation, will be a discovery effort in the relapsed NB genome, correlating sequence variations with oncogenic potential and prioritizing next-generation ALK inhibitors for preclinical and clinical testing. Aim 2 is devoted to elucidate mechanisms of intrinsic resistance to crizotinib that will allow for rational prediction of combinatorial therapies for further evaluation. The final Aim will garner the preclinical justification required to move combination therapies to the clinic, building on our extensive preliminary data of synergistic drug interactions in crizotinib-resistant models. We consider this project significant because it will result in identification of key oncogenic vulnerabilities in NB cells, biomarkers of response and resistance which will be integrated into phase 1 trials, and the proof-of- concept required to justify alternative ALK inhibition strategies for early phase clinical trial development.

描述（由申请人提供）：神经母细胞瘤（NB）仍然是儿童癌症死亡的主要原因。幸存下来的儿童会留下长期的副作用，其中许多可能危及生命。在这个治疗更加理性的时代，人们付出了大量努力来确定最佳靶点。我们发现 ALK 癌基因的激活突变是遗传性 NB 的主要原因，而体细胞获得性突变和扩增事件通常会驱动散发性肿瘤的恶性过程。这是该项目第一阶段的动机，我们随后证明常见的 ALK 突变会导致不同的激酶激活和对 ATP 竞争性抑制剂的不同敏感性。这项工作将 ALK 确立为 NB 中易于处理的分子靶标，并导致现已完成的儿科 1 期试验和正在进行的克唑替尼（FDA 批准的唯一 ALK 抑制剂）的 2 期试验。我们的 R01 前 4 年的结果显示了 NB 中 ALK 激活的复杂性，并证明抑制突变激酶结构域比淋巴瘤和肺癌中存在的融合蛋白更具挑战性。这为本研究计划的长期目标提供了动力，即开发旨在有效抑制 ALK 介导的信号传导的新型治疗策略。主要目标是为新诊断的 ALK 突变 NB 患者的治疗分层制定应答者假设，阐明克唑替尼耐药机制，并确定临床规避策略。这里要探讨的中心假设是，只有在阐明患者中发现的 ALK 改变的临床意义以及驱动内在耐药性的机制后，才能成功开发合理且有效的 ALK 抑制策略。其动机是迫切需要提高高危 NB 生存率并减少与治疗相关的发病率。我们将在三个具体目标上检验我们的中心假设：1) 定义患者源性 ALK 改变的功能后果； 2) 确定对 ALK 抑制的敏感性和抗性机制； 3) 开发针对 ALK 信号通路的合理治疗组合以克服耐药性。第一个目标基于最近未发表的数据，显示了 ALK 激活的各种替代遗传机制，将是在复发 NB 基因组中进行发现工作，将序列变异与致癌潜力相关联，并优先考虑下一代 ALK 抑制剂进行临床前和临床测试。目标 2 致力于阐明克唑替尼内在耐药机制，以便合理预测组合疗法以进行进一步评估。最终目标将获得将联合疗法转移到临床所需的临床前理由，建立基于我们在克唑替尼耐药模型中协同药物相互作用的广泛初步数据。我们认为该项目意义重大，因为它将导致鉴定 NB 细胞中的关键致癌脆弱性、反应和耐药的生物标志物（将整合到 1 期试验中）以及证明替代 ALK 抑制策略合理性所需的概念验证用于早期临床试验开发。