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

• 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
• 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

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.

项目摘要/戒律 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患者 肺癌（NSCLC）具有可能可切除的早期NSCLC。尽管完全切除， 大约50％的II期和III NSCLC患者复发，死于转移性NSCLC。没有 可靠的生物标志物可以预测早期NSCLC的不良结局。分子靶向疗法和 免疫检查点封锁靶向编程死亡-1（PD-1）或编程死亡配体1（PD-L1） 已经显着改善了转移性NSCLC患者的结局，这些药物现在是 标准治疗后，正在进行早期肺癌的临床试验。国家癌症研究所 （NCI）发起了一项雄心勃勃的多中心研究，即辅助肺癌富集标记 识别和测序（炼金术士），以筛选近8000名完全切除的NSCLC患者 确定表皮生长因子受体（EGFR）酪氨酸激酶（TK）中激活突变的人 以及在变性淋巴瘤激酶（ALK）中的重排以研究厄洛替尼和克里佐替尼的作用， 分别。那些缺乏EGFR突变或ALK重排的人参与了 比较Nivolumab的随机试验，Nivolumab（PD-1的抑制剂）与观察。炼金术士基因组学 工作组计划研究近2000次的肿瘤全基因组，外部和转录组 未参加干预试验（炼金术士筛查研究）的患者和所有参加的患者 在三个炼金术士治疗试验中。这套试验与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预后的作用 与切除的NSCLC。我们提出了一个蛋白质组学转化研究中心（PTRC）来研究 华盛顿大学学校的蛋白质组学变化在切除的早期NSCLC共同领导 医学（WUSM）和广泛研究所以及隶属于NCI资助的国家的调查员 临床试验网络（NCTN）支持临床试验的炼金术症套件。我们的总体目标是 将基于质谱的全局和靶向蛋白质组学分析应用于患者衍生的肿瘤 使用体细胞癌基因组和转录组和转录组和 临床特征。这些发现将转化为有针对性的测定，以预测复发 治疗后。由于炼金术症的研究仍在进行中，并且招募相对较少 患者与其他研究相比，我们不会在此提案中包括这些样本。这三个目标 项目将开发预后评估工具，以预测已切除的NSCLC治疗患者的复发 使用标准的铂双化化疗（AIM 1），标准铂双运动疗法和Nivolumab （AIM 2）和使用蛋白质组学的标准铂双化疗和Erlotinib（AIM 3）。