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，继续成为非小细胞肺癌（NSCLC）的个性化治疗方法。例如，表皮生长因子受体（EGFR）中具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。然而，许多肺癌患者（约50%）的肿瘤没有已知的致癌驱动突变;因此，他们的治疗选择有限。为了扩大这些患者的治疗药物库，将使用蛋白磷酸化和激酶活性水平的定量测量来检查每个肿瘤中的主要信号传导途径，与从同一肺叶切除的相应正常肺组织相比。液相色谱-多反应监测质谱法（LC-MRM）将用于监测超过260种酪氨酸磷酸化肽，以生成磷酸化谱，并使用基于活性的蛋白质谱对超过160种肽进行标记和亲和纯化，以指示活性激酶的水平。我们一起努力， 这些数据将用于指示激活的途径并推断可使用现有激酶抑制剂破坏的枢纽。这个用于患者评估的定量平台将寻求治疗无已知驱动突变的NSCLC的选择，最终目标是定义一个可以在活检中检测的候选生物标志物的小列表。这种探索肺癌信号传导的系统方法的发展也将为定量质谱分析信号网络和LC-MRM的临床实用性提供见解。