Proteogenomic Predictors of Recurrence in Non-small Cell Lung Cancer

非小细胞肺癌复发的蛋白质基因组预测因素

基本信息

批准号：
10459716
负责人：
STEVEN A CARR
金额：
$ 108.43万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-13 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10459716
关键词：
Adenocarcinoma Cell Adjuvant Assessment tool Biological Assay Biological Markers Cancer Etiology Center for Translational Science Activities Cessation of life Characteristics Clinical Clinical Trials Coupled Data Data Analyses Enrollment Epidermal Growth Factor Receptor Erlotinib Excision Funding Genome Genomics Human Institutes Intervention Trial Lung Adenocarcinoma Machine Learning Malignant Neoplasms Malignant neoplasm of lung Maps Mass Spectrum Analysis Multicenter Studies Mutation National Cancer Institute National Clinical Trials Network Nivolumab Nodal Non-Small-Cell Lung Carcinoma Nonmetastatic Operative Surgical Procedures Outcome Pathway interactions Patient-Focused Outcomes Patients Peptides Phosphorylation Platinum Post-Translational Protein Processing Postoperative Period Prognostic Factor Prognostic Marker Protein Tyrosine Kinase Proteins Proteome Proteomics Randomized Recurrence Relapse Research Personnel Resectable Resected Risk Risk Factors Role Sampling Specimen Squamous Cell Lung Carcinoma Systemic Therapy Testing Therapeutic Trials Tissue Sample Training Translating Universities Validation Washington anaplastic lymphoma kinase assay development base biomarker identification cancer cell cancer genome chemotherapy cohort crizotinib exome genomic data immune checkpoint blockade improved improved outcome inhibitor lymphatic Invasion medical schools molecular targeted therapies mutant outcome prediction patient subsets predictive marker prognostic prognostic model programmed cell death ligand 1 programmed cell death protein 1 proteogenomics randomized trial relapse prediction relapse risk screening standard of care support network transcriptome transcriptomics trial comparing tumor whole genome working group

项目摘要

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.

项目概要/摘要肺癌是全球癌症相关死亡的主要原因。近三分之一的患者患有非小细胞肺癌 (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。没有预测早期非小细胞肺癌不良结局的可靠生物标志物。分子靶向治疗和针对程序性死亡-1 (PD-1) 或程序性死亡配体-1 (PD-L1) 的免疫检查点阻断显着改善了转移性非小细胞肺癌患者的预后，这些药物现已上市在标准治疗后正在进行早期肺癌的临床试验。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，即辅助肺癌富集标记物识别和测序 (ALCHEMIST)，筛查近 8000 名完全切除的 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。那些患有缺乏 EGFR 突变或 ALK 重排的肿瘤的人被邀请参加一项将 PD-1 抑制剂纳武单抗 (nivolumab) 与观察结果进行比较的随机试验。炼金术士基因组学工作组计划研究近2000个肿瘤全基因组、外显子组和转录组未参加干预试验（ALCHEMIST 筛选研究）的患者以及所有入组患者在三项 ALCHEMIST 治疗试验中。这套试验使用基因组分析生成的数据提供了一个独特的机会来探索癌症蛋白质组在预测患者结果中的作用切除非小细胞肺癌。我们提议建立一个蛋白质基因组转化研究中心（PTRC）来研究由华盛顿大学医学院共同领导的切除早期非小细胞肺癌的蛋白质组学改变医学 (WUSM) 和布罗德研究所以及隶属于 NCI 资助的国家实验室的研究人员临床试验网络 (NCTN) 支持 ALCHEMIST 临床试验套件。我们的首要目标是将基于质谱的全局和靶向蛋白质组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生物标志物的材料临床特征。这些发现将转化为靶向检测以预测复发治疗后。由于 ALCHEMIST Crizotinib 研究仍在进行中，并且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中。本次活动的三大目的该项目旨在开发预后评估工具来预测接受切除的 NSCLC 患者的复发标准铂类双药化疗（目标 1）、标准铂类双药化疗和纳武单抗（目标 2），以及使用蛋白质基因组学的标准铂双药化疗和厄洛替尼（目标 3）。