Molecular Biomarkers of Small Cell Lung Cancer Behaviour

项目摘要 摘要小细胞肺癌(Sclc)是一种转移频繁、病情恶劣的破坏性疾病。 结果。多年的研究和创新的治疗方法提高了对小细胞肺癌的认识 生物学和症状控制，但在早期诊断和肿瘤领域几乎没有增加 行为。这个项目的主要目标是发现和验证副本数量的模式 与临床相关结局相关的蛋白表达的改变，如 小细胞肺癌的诊断、治疗反应及预后。我们的特定假设背后的 拟议的研究是，SCLC携带大量拷贝数改变， 确定与肿瘤进展有关的蛋白质的表达谱， 对治疗的反应和携带预后信息。我们将使用三种方法来测试 假设。首先，我们建议通过独特的深入分析来检验这一假设 采用高通量技术，根据临床结果精心选择小细胞肺癌组织。 我们将使用基因组和蛋白质组相结合的分析来选择最可量化的候选 小细胞肺癌中的生物标记物特征。这些分子特征将导致对肺的更深入的了解 肿瘤发生、肿瘤行为和改进的诊断工具，以使更早和更有针对性 治疗干预，试图降低小细胞肺癌的发病率和死亡率。 其次，我们将对小细胞肺癌和小细胞肺癌进行详细的比较分子分析 NSCLC和解决诊断特征的特异性。我们将使用详细的生物统计学 解决签名稳定性的方法，这将突出几个新的基因/蛋白质 与疾病相关，并强调了一个关键的分子途径，可能在 未来疗法的设计。第三，因为我们的初步数据表明， 小细胞肺癌进展中的局灶性黏附途径，我们建议开始研究这一途径 并确定它可能如何影响SCLC行为。为了实现我们的目标，我们建议 以下具体目标：具体目标1：我们建议确定特定于SCLC的候选人 通过详细的分子分析确定诊断、进展时间和生存的生物标志物。我们 将检验这样的假设，即SCLC携带决定表达的基因组改变 与肿瘤进展有关的蛋白质图谱。阵列CGH与鸟枪蛋白质组学 代表我们的关键发现平台。具体目标2：我们建议执行一项详细的 小细胞肺癌和非小细胞肺癌的比较基因组和蛋白质组学分析 潜在的新分子诊断靶点。我们将测试特定分子的假设 从细致入微的差异分子中可以推断出途径和潜在的治疗靶点 分析。我们战略背后的概念是使用各种方法来分析 来自同一患者的临床相关样本，以及系统整合 生物学和临床数据。具体目标3：我们建议调查震源 从我们的初步数据中发现的黏附信号通路在小细胞肺癌中被激活。我们 将确认小细胞肺癌中FAK的扩增，确定组织芯片中的表达水平， 并通过阻断和敲除或过度表达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、运动和侵袭的影响。 属性。我们将在组织中确定这一分子途径的临床相关性。 用于治疗反应、疾病进展和总存活率的微阵列(TMA)。

Project Summary 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.