Translational phosphoproteomics for lung cancer

描述（由申请人提供）：肺癌是全球癌症相关死亡的主要原因。根据目前的检测策略和治疗方法，去年确诊的肺癌患者中只有16%能存活五年。肺癌是广泛的遗传变化的结果，其中许多间接影响蛋白激酶信号通路，破坏细胞增殖和凋亡的正常稳态。蛋白激酶是肺癌治疗的重要靶点。本文提出的实验的目的是开发和验证磷酸蛋白质组学中的定量方法，这些方法能够探测与患者结局相关的肺肿瘤中细胞信号传导的差异。为此，我们将i）开发用于临床肺癌标本的定量磷酸化蛋白质组学技术，ii）开发靶向临床相关激酶底物的磷酸化多反应监测（p-MRM）方法，iii）部署这些方法来研究来自有限队列的非小细胞肺癌患者的肿瘤细胞信号传导差异。我们预计，这里提出的实验的成功进行将提供翻译科学家和胸部肿瘤学家与一个全新的层面的生物医学信息，这将使新的治疗策略的发现，改善患者的反应性评估激酶抑制剂治疗在分子水平上，并允许高度个性化的决定，对病人的护理。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer-related deaths worldwide. Based on status quo detection strategies and therapies, only 16% of patients diagnosed last year with lung cancer will survive for five years. Lung cancer is the result of a wide range of genetic changes, many of which indirectly affect protein kinase signaling pathways that disrupt the normal homeostasis of cell proliferation and apoptosis. Protein kinases are now an important class of targets for lung cancer therapy. The purpose of the experiments proposed here is to develop and validate quantitative methods in phosphoproteomics capable of probing differences in cellular signaling in lung tumors that correlate with patient outcomes. To do this, we will i) develop a quantitative phosphoproteomics technology for clinical lung cancer specimens, ii) develop phospho-multiple reaction monitoring (p-MRM) methods that target substrates of clinically relevant kinases, and iii) deploy these methods to study differences in cellular signaling in tumors from a limited cohort of non-small cell lung cancer patients. We anticipate that the successful conduct of the experiments proposed here will provide translational scientists and thoracic oncologists with an entirely new dimension of biomedical information which will enable the discovery of new treatment strategies, improve assessments of patient responsiveness to kinase inhibitor therapies at the molecular level, and allow for highly individualized decisions regarding patient care.