Quantification of Tyrosine Phosphorylation and Kinase Expression in NSCLC

NSCLC 中酪氨酸磷酸化和激酶表达的定量

• 批准号: 8583483
• 负责人: John M Koomen
• 金额: $ 21.99万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-02 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8583483
• 关键词: Affinity Labels; Basic Science; Bioinformatics; Biological Assay; Biological Markers; Biometry; Biopsy; Biopsy Specimen; Biotin; Cancer Biology; Cancer Patient; Cancer cell line; Caring; Cell Line; Clinical; Clinical Trials; Companions; Complement; Data; Data Correlations; Data Set; Detection; Development; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Evaluation; Event; Exons; Freezing; Gefitinib; Gene Expression; Genetic; Goals; Grant; Histocompatibility Testing; Immunoprecipitation; Individual; Knowledge; Label; Light; Liquid Chromatography; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Measurement; Measures; Methods; Molecular Profiling; Monitor; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenic; Outcome; Pathway interactions; Patients; Pattern; Peptides; Pharmaceutical Preparations; Phase; Phosphoric Monoester Hydrolases; Phosphorylated Peptide; Phosphorylation; Phosphotransferases; Phosphotyrosine; Protein Array; Protein Kinase Protein Phosphorylation; Protein Tyrosine Kinase; Proteomics; Research; Resected; Resistance; Sampling; Signal Pathway; Signal Transduction; Specimen; Structure of parenchyma of lung; Techniques; Testing; Therapeutic; Therapeutic Agents; Tissues; Transcript; Translations; Tumor Biology; Tumor Tissue; Tyrosine; Tyrosine Phosphorylation; Work; activity-based protein profiling; affinity labeling; base; cancer therapy; drug sensitivity; effective therapy; improved; inhibitor/antagonist; insight; kinase inhibitor; lung lobe; multiple reaction monitoring; mutant; novel; public health relevance; research study; tool; treatment strategy; tumor

DESCRIPTION (provided by applicant): Targeted therapy, specifically through kinase inhibition, continues to emerge as a method for personalized therapy in non-small cell lung cancer (NSCLC). As an example, patients with driver mutations in the epidermal growth factor receptor (EGFR) can be treated with Erlotinib or other targeted EGFR inhibitors to improve their outcomes. However, many lung cancer patients (~50%) have tumors that do not have known oncogenic driver mutations; subsequently, their treatment options are limited. In order to expand the arsenal of therapeutic agents for these patients, quantitative measurements of protein phosphorylation and kinase activity levels will be used to examine the dominant signaling pathways in each tumor, when compared with the corresponding normal lung tissue resected from the same lobe of the lung. Liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM) will be used to monitor more than 260 tyrosine-phosphorylated peptides to generate phosphorylation profiles and more than 160 peptides labeled and affinity purified using activity-based protein profiling to indicate the levels of active kinases. Together, these data will be used to indicate activated pathways and infer hubs that can be disrupted using existing kinase inhibitors. This quantitative platform for patient assessment will seek options for treatment of NSCLC with no known driver mutations, with the ultimate goal of defining a small list of candidate biomarkers that can be tested in biopsies. The development of this systematic approach to explore signaling in lung cancer will also provide insights into the analysis of signaling networks with quantitative mass spectrometry and the clinical utility of LC-MRM.

描述（由申请人提供）：靶向治疗，特别是通过激酶抑制作用，继续作为非小细胞肺癌（NSCLC）个性化治疗的一种方法。例如，表皮生长因子受体（EGFR）中患有驱动突变的患者可以用厄洛替尼或其他靶向EGFR抑制剂治疗，以改善其结果。但是，许多肺癌患者（约50％）的肿瘤尚无已知的致癌驱动突变。随后，他们的治疗选择受到限制。为了扩大这些患者的治疗剂的武器库，与从同一肺部同一叶的相应正常肺组织相比，将使用蛋白质磷酸化和激酶活性水平的定量测量来检查每个肿瘤中的显性信号传导途径。液相色谱 - 形成反应监测质谱法（LC-MRM）将用于监测超过260个酪氨酸磷酸化的肽，以产生磷酸化谱，并使用基于活性的蛋白质谱图标记的160多种肽和亲和力纯化，以表明活性激酶的水平。一起， 这些数据将用于指示使用现有激酶抑制剂可以破坏的活化途径和推断枢纽。这种定量的患者评估平台将寻求对NSCLC治疗的选择，而没有已知的驾驶员突变，其最终目的是定义可以在活检中进行测试的候选生物标志物的少量列表。这种系统探索肺癌信号传导的系统发展还将提供有关具有定量质谱和LC-MRM的临床实用性的信号网络分析的见解。