Proteogenomic Predictors of Recurrence in Non-small Cell Lung Cancer

项目概要/摘要 肺癌是全球癌症相关死亡的主要原因。近三分之一的非小细胞肺癌患者 肺癌（NSCLC）表现为可能可切除的早期NSCLC。尽管完全切除， 大约50%的II期和III期NSCLC患者复发并死于转移性NSCLC。没有 可靠的生物标志物来预测早期NSCLC的不良结局。分子靶向治疗和 靶向程序性死亡-1（PD-1）或程序性死亡配体-1（PD-L1）的免疫检查点阻断 已经显著改善了转移性NSCLC患者的预后，这些药物现在 正在接受标准治疗后的早期肺癌临床试验。美国国家癌症研究所 (NCI)启动了一项雄心勃勃的多中心研究， 鉴定和测序（ALCHEMIST），筛查近8000例完全切除的NSCLC患者 识别表皮生长因子受体（EGFR）酪氨酸激酶（TK）激活突变的患者 和间变性淋巴瘤激酶（ALK）重排，以研究厄洛替尼和克唑替尼的作用， 分别那些缺乏EGFR突变或ALK重排的肿瘤患者参加了一项研究， 随机试验比较nivolumab，PD-1的抑制剂观察。炼金术士基因组学 工作组计划研究近2000年来的肿瘤全基因组、外显子组和转录组。 未参加干预试验（ALCHEMIST筛选研究）的患者和所有入组的患者 在三个炼金术士治疗试验中。这套试验的数据是通过基因组分析产生的 为探索癌症蛋白质组在预测患者预后中的作用提供了独特的机会 切除的NSCLC。我们建议建立一个蛋白基因组转化研究中心（PTRC）， 由华盛顿大学医学院共同领导的切除的早期NSCLC中的蛋白基因组学改变 医学（WUSM）和布罗德研究所沿着与研究人员隶属于国家癌症研究所资助的国家 临床试验网络（NCTN）支持ALCHEMIST系列临床试验。我们的首要目标是 将基于质谱的全局和靶向蛋白质组学分析应用于患者来源的切除肿瘤 使用体细胞癌基因组和转录组改进预测性生物标志物的材料， 临床特征这些发现将被转化为靶向检测，以预测复发 治疗后。由于ALCHEMIST克唑替尼研究仍在进行中，入组人数相对较少 与其他研究相比，我们不会将这些样本纳入本提案。这三个目标 该项目旨在开发预后评估工具，以预测接受切除治疗的NSCLC患者的复发 联合标准铂双联化疗（aim 1）、标准铂双联化疗和纳武单抗 (aim 2），和标准铂双联化疗和厄洛替尼（目的3）使用蛋白质基因组学。

PROJECT SUMMARY/ABSTARCT Lung cancer is a leading cause of cancer-related death globally. Nearly a third of patients with non-small cell lung cancer (NSCLC) present with potentially resectable early-stage NSCLC. Despite complete resection, approximately 50% of patients with stage II and III NSCLC recur and die from metastatic NSCLC. There are no reliable biomarkers to predict poor outcomes in early-stage NSCLC. Molecularly targeted therapies and immune checkpoint blockade targeting programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) have significantly improved the outcomes of patients with metastatic NSCLC, and these agents are now undergoing clinical trials in early-stage lung cancer following standard therapy. The National Cancer Institute (NCI) has launched an ambitious multicenter study, the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing (ALCHEMIST), to screen nearly 8000 patients with completely resected NSCLC to identify those with activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) and rearrangements in anaplastic lymphoma kinase (ALK) to investigate the role of erlotinib and crizotinib, respectively. Those with tumors lacking EGFR mutation or ALK rearrangement were offered participation in a randomized trial comparing nivolumab, an inhibitor of PD-1 to observation. The ALCHEMIST Genomics Working Group is planning to study the tumor whole genomes, exomes, and transcriptomes from nearly 2000 patients who did not participate in the intervention trials (ALCHEMIST Screening Study) and all those enrolled in the three ALCHEMIST therapeutic trials. This suite of trials with data generated using genomic analyses provides a unique opportunity to explore the role of the cancer proteome in predicting outcomes in patients with resected NSCLC. We propose a Proteogenomic Translational Research Center (PTRC) to study the proteogenomic alterations in resected early-stage NSCLC co-led by the Washington University School of Medicine (WUSM) and the Broad Institute along with investigators affiliated with the NCI-funded National Clinical Trials Network (NCTN) supporting the ALCHEMIST suite of clinical trials. Our overarching objective is to apply mass spectrometry-based global and targeted proteomic analyses to patient-derived resected tumor material to improve upon the predictive biomarkers using somatic cancer genome and transcriptome and clinical characteristics. These discoveries will be translated into targeted assays to predict recurrence following therapy. Since the ALCHEMIST Crizotinib study is still ongoing and has enrolled relatively fewer patients compared to other studies, we will not include those samples in this proposal. The three aims of this project are to develop prognostic assessment tools to predict relapse in patients with resected NSCLC treated with standard platinum doublet chemotherapy (aim 1), standard platinum doublet chemotherapy and nivolumab (aim 2), and standard platinum doublet chemotherapy and erlotinib (aim 3) using proteogenomics.