Molecular Biomarkers of Small Cell Lung Cancer Behaviour

描述(由申请人提供)： 小细胞肺癌(SCLC)是一种转移率高、预后差的疾病。多年的研究和创新治疗提高了对小细胞肺癌生物学和症状控制的理解，但在早期诊断和肿瘤行为方面几乎没有增加。这个项目的主要目标是发现和验证与小细胞肺癌的诊断、治疗反应和预后等临床相关结果相关的拷贝数改变和蛋白表达的模式。我们提出的研究背后的特定假设是，SCLC携带许多拷贝数改变，这些改变决定了与肿瘤进展、治疗反应和携带预后信息有关的蛋白质的表达谱。我们将使用三种方法来检验这一假设。首先，我们建议通过对精心挑选的小细胞肺癌组织进行独特的深度分析来验证这一假设，该分析基于高通量技术的临床结果。我们将使用基因组和蛋白质组相结合的分析来选择SCLC中最可量化的候选生物标记物签名。这些分子特征将导致对肺肿瘤发生、肿瘤行为的更深入了解，并改进诊断工具，以便进行更早、更有针对性的治疗干预，试图降低小细胞肺癌的发病率和死亡率。其次，我们将在小细胞肺癌和非小细胞肺癌之间进行详细的比较分子分析，并解决诊断特征的特异性。我们将使用详细的生物统计学方法来解决签名的稳定性，这将突出几个与疾病相关的新基因/蛋白质，并强调一个关键的分子途径，这可能在未来的治疗设计中提供希望。第三，由于我们的初步数据显示粘着斑通路在小细胞肺癌进展中具有独特的作用，我们建议开始研究这一通路，并确定它可能如何影响小细胞肺癌的行为。为了实现我们的目标，我们提出了以下具体目标：具体目标1：我们建议通过详细的分子分析来确定小细胞肺癌诊断、进展时间和生存的特异性候选生物标记物。我们将验证这样的假设，即SCLC携带基因组改变，该改变决定了与肿瘤进展有关的蛋白质的表达谱。阵列CGH和鸟枪蛋白质组学是我们的关键发现平台。具体目标2：我们建议在小细胞肺癌和非小细胞肺癌之间进行详细的比较基因组和蛋白质组分析，以确定潜在的新的分子诊断靶点。我们将检验这一假设，即特定的分子途径和潜在的治疗靶点可以从仔细的差异分子分析中推断出来。我们的策略背后的概念是使用各种方法来分析从同一患者获得的临床相关样本，以及生物和临床数据的系统集成。具体目标3：我们建议从我们的初步数据中研究在小细胞肺癌中激活的焦点黏附信号通路。我们将确认FAK在小细胞肺癌中的扩增，确定FAK在组织芯片中的表达水平，并通过阻断和敲除FAK，或过表达FAK来确定FAK在小细胞肺癌中的作用。我们将主要评估这些变化对细胞黏附、运动和侵袭特性的影响。我们将在组织微阵列(TMA)中确定这一分子途径的临床相关性，以确定治疗反应、疾病进展和总存活率。

DESCRIPTION (provided by applicant): Small cell lung cancer (SCLC) is a devastating illness with frequent metastases and poor outcome. Years of research and innovative treatment yielded improved understanding of SCLC biology and control of symptoms, but little increase in the area of early diagnosis and tumor behavior. The major goals of this project are to discover and validate patterns of copy number alterations and of protein expression associated with clinically relevant outcomes such as diagnosis, response to therapy and prognosis of SCLC. Our specific hypothesis behind the proposed research is that SCLCs carry a number of copy number alterations that determines the expression profiles of proteins that are implicated in tumor progression, response to therapy and carry prognostic information. We will use three approaches to test the hypothesis. First, we propose to test this hypothesis with a unique in depth analysis of carefully selected SCLC tissues based on clinical outcomes with high throughput technologies. We will use combined genomic and proteomic analysis to select the most quantifiable candidate biomarker signatures in SCLC. These molecular signatures will lead to greater insight into lung tumorigenesis, tumor behavior and improved diagnostic tools to allow earlier and more targeted therapeutic interventions in an attempt to reduce the morbidity and mortality from SCLC. Second, we will perform a detailed comparative molecular analysis between SCLC and NSCLCs and address specificity of diagnostic signatures. We will use detailed biostatistical approaches to address stability of the signature which will highlight several novel genes/proteins associated with the disease and underscore a key molecular pathway that may offer promise in the design of future therapies. Third, because our preliminary data suggest a distinct role of focal adhesion pathway in SCLC progression, we propose to begin investigating this pathway and determine how it may impact on SCLC behavior. To achieve our goals, we propose the following specific aims: Specific Aim 1: We propose to identify SCLC-specific candidate biomarkers of diagnosis, time to progression and survival by detailed molecular analysis. We will test the hypothesis that SCLCs carry genomic alterations that determines the expression profiles of proteins that are implicated in tumor progression. Array CGH and shotgun proteomics represent our key discovery platforms. Specific Aim 2: We propose to perform a detailed comparative genomic and proteomic analysis between SCLC and NSCLCs to identify potential new molecular diagnostic targets. We will test the hypothesis that specific molecular pathways and potential therapeutic targets can be deduced from careful differential molecular analysis. The concept behind ourstrategy is the use of various approaches for theanalysis of clinically relevant samples obtainedfrom the same patient, along with the systematic integration of the biological and clinical data. Specific Aim 3: We propose to investigate the focal adhesion signaling pathway that emerges from our preliminary data as activated in SCLC. We will confirm FAK amplification in SCLC, determine the expression level in tissue microarrays, and determine a role of FAK in SCLC by blocking and knocking down, or overexpressing FAK. We will assess the impact of these changes primarily on cell adhesion, motility and invasion properties. We will determine the clinical correlates of this molecular pathway in tissue microarrays (TMA) for response to therapy, progression of disease and overall survival.