P-1: Molecular Signatures for Individualizing Lung Cancer Therapy

来自患者的非小细胞肺癌（NSCLC）在对化疗的敏感性或抗性方面表现出很大的差异。 化疗和靶向药物。我们假设这些差异将反映在肿瘤mRNA 和蛋白质特征，并且这些特征可用于提高治疗的有效性。 心理治疗最终目标是开发和使用这些特征来确定最佳的治疗方法 对于那个人来说。然而，为了实现这一目标，迫切需要临床前模型， 开发这些特征并测试新疗法。该项目建议使用一个大型面板的NSCLC细胞 细胞系和异种移植物，以系统地测量临床前治疗反应表型， 这些反应的mRNA和蛋白质生物标志物特征，然后在其他细胞系中验证这些， 异种移植物和患者肿瘤标本。我们还将在患者中鉴定mRNA和蛋白质生物标志物， 样本，并在临床前模型中对其进行测试，最终产生经验证的生物标志物， 预测患者和验证的临床前模型。具体目标是：目标1）定量测量 在一个大型（约100）人NSCLC细胞系和异种移植物中的药物敏感性/耐药表型 （~50），包括直接从患者肿瘤中制备的异种移植物，而不进行干预培养，并比较 体外药物反应表型与原位（肺）异种移植物的表型;目的2）鉴定微阵列 基于mRNA和反相蛋白质阵列（RPPA）的对治疗药物应答的表达特征 使用这些特征，我们将在一个新的NSCLC“测试”集中预测药物反应。 细胞系和异种移植物，并进行“临床前试验”，比较标准的非选择性的方法， 治疗（NST）与特征选择治疗（SST）;目的3）验证这些特征， 临床注释为对标准和靶向药物有反应的NSCLC标本（约100份冷冻标本和 200份福尔马林固定石蜡包埋标本）。我们还将独立开发响应签名 并使用临床前模型和其他患者模型测试这些预测能力 标本最后，我们将测试其他调查人员报告的签名，并整合最具信息性的签名。 用我们自己的从所有这些，我们将开发新的方法来选择最好的可用疗法， 个体化患者，建立临床前人类肿瘤模型系统，用于系统测试新药， 并开发签名以指导其最有效的使用。该项目汇集了多学科 基础和临床研究人员团队，拥有相当多的初步数据和临床注释的肿瘤 供研究的标本。它利用病理学、生物统计学和生物信息学核心， 与此SPORE中的多个其他项目以及多个SPORE间合作的核心。

Non-small cell lung cancers (NSCLCs) from patients exhibit large differences in sensitivity or resistance to chemotherapy and targeted drugs. We hypothesize that these differences will be reflected in tumor mRNA and protein signatures prior to treatment, and that these signatures can be used to improve the effectiveness of therapy. The eventual goal to develop and use such signatures to determine the best available treatment for that individual. To move towards this goal, however, there is a critical need for preclinical models to develop such signatures and test new therapies. This project proposes to use a large panel of NSCLC cell lines and xenografts to systematically measure preclinical therapy response phenotypes, define associated mRNA and protein biomarker signatures of these responses, and then validate these in other cell lines, xenografts, and patient tumor specimens. We will also identify mRNA and protein biomarkers in patient specimens and test them in the preclinical models, eventually resulting in validated biomarkers for response prediction in patients and validated preclinical models. Specific Aims are: Aim 1) To measure quantitative drug sensitivity/resistance phenotypes in a large panel (-100) of human NSCLC cell lines and xenografts (~50), including xenografts made directly from patient tumors without intervening culture, and compare in vitro drug response phenotypes with those of orthotopic (lung) xenografts; Aim 2) To identify microarray mRNA and reverse phase protein array (RPPA)-based expression signatures of response to therapeutic agents in NSCLC lines; using these signatures we will predict drug responses in a new "test" set of NSCLC cell lines and xenografts, and conduct a "preclinical trial" comparing the approach of standard non-selected therapy (NST) versus signature-selected therapy (SST); Aim 3) To validate these signatures on available NSCLC specimens clinically annotated as to response to standard and targeted agents (~100 frozen and 200 formalin-fixed paraffin embedded specimens). We will also independently develop response signatures directly from patient samples and test these for predictive ability using preclinical models and other patient specimens. Finally, we will test signatures reported by other investigators and integrate the most informative with our own. From all of this we will develop new methods to select the best available therapies for individual patients, establish a preclinical human tumor model system for systematically testing new drugs, and develop signatures to guide their most efficient use. This project has assembled a multidisciplinary team of basic and clinical investigators, has considerable preliminary data, and clinically annotated tumor specimens for study. It makes use of the Pathology, Biostatistics, and Bioinformatics Cores and interacts with multiple other projects in this SPORE as well as nucleating multiple inter-SPORE collaborations.