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5年。肺癌是多种遗传变化的结果，其中许多遗传变化间接影响蛋白激酶信号通路，从而破坏细胞增殖和凋亡的正常稳态。蛋白激酶现在是肺癌治疗的重要靶点。本文提出的实验目的是开发和验证磷蛋白质组学的定量方法，该方法能够探测肺肿瘤中与患者预后相关的细胞信号传导差异。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)开发针对临床相关激酶底物的磷酸化多反应监测（p-MRM）方法，以及iii)利用这些方法研究有限的非小细胞肺癌患者肿瘤中细胞信号传导的差异。我们预计，这里提出的实验的成功实施将为转化科学家和胸部肿瘤学家提供一个全新的生物医学信息维度，这将有助于发现新的治疗策略，提高患者对激酶抑制剂治疗在分子水平上的反应性评估，并允许高度个性化的患者护理决策。

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.