Proteogenomics-driven therapeutic discovery in hepatocellular carcinoma

项目摘要 肝细胞癌（HCC）是世界范围内癌症相关死亡的第三大原因， 治疗选择有限。我们迫切需要完全理解 为了确定新的有效的生物标志物，药物靶点和治疗剂， HCC的预后和治疗。蛋白质是细胞的功能分子，许多临床验证 生物标志物和大多数药物靶点是蛋白质;然而，癌症组学研究主要依赖于基因组学。 平台通过融合基因组学和基于质谱（MS）的蛋白质组学， 蛋白质基因组学提供了一个机会，更全面地了解体细胞基因组如何激活异常 驱动癌症发病机制的蛋白质网络。一个主要的国家癌症研究所（NCI）资助的倡议， 临床蛋白质组学肿瘤分析联盟（CPTAC），以及最近成立的国际 癌症蛋白基因组联盟（ICPC）正在促进一种整合的蛋白基因组学方法， 假设产生更合理的治疗假设和新一代蛋白质生物标志物。中央 本申请的目的是在美国的CPTAC团队和ICPC之间建立合作 在中国的团队，使蛋白基因组学驱动的治疗发现，在肝炎B病毒相关 (HBV+）HCC，占中国HCC病例的85%。两个团队带来互补的专业知识 这是成功进行HCC蛋白质组学研究所必需的。中国队已经产生了最多的 通过将蛋白基因组学分析应用于肝癌， 中国HBV+ HCC队列（CHCC-HBV）159例，通过 两个团队之间的合作。在这个应用程序中，美国团队将进行深度计算， 分析蛋白质组学数据，以生成预后模型和治疗假设，这将是 中国团队在细胞系、动物模型和临床标本中进行了实验验证。我们的具体 目的是：目的1）开发和验证基于蛋白质的预后模型;目的2）识别和验证 亚型特异性因果驱动因素和治疗策略;以及目的3）表征 乙型肝炎病毒+肝细胞癌。该项目的成功完成将导致对HCC生物学的新知识以及新的 HBV+ HCC的预后和治疗策略。同时，实验验证的计算方法 本项目所开发的新技术将广泛应用于其他癌症和其他非癌症疾病的研究。

Project Summary Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, and therapeutic options are limited. There is a pressing need to fully understand the molecular mechanisms underlying the disease in order to identify new effective biomarkers, drug targets, and therapeutic agents for the prognosis and treatment of HCC. Proteins are the functional molecules of the cell, and many clinically validated biomarkers and most drug targets are proteins; however, cancer omics studies have relied primarily on genomic platforms. By melding genomics with mass spectrometry (MS)-based proteomics, the new field of proteogenomics provides an opportunity to more completely understand how somatic genomes activate aberrant protein networks that drive cancer pathogenesis. A major National Cancer Institute (NCI)-funded initiative, the Clinical Proteomics Tumor Analysis Consortium (CPTAC), and the more recently established International Cancer Proteogenome Consortium (ICPC), are promoting an integrated proteogenomics approach that is postulated to produce sounder therapeutic hypotheses and a new generation of protein biomarkers. The central purpose of this application is to forge a collaboration between a CPTAC team in the US and an ICPC team in China to enable proteogenomics-driven therapeutic discoveries in hepatitis B virus-related (HBV+) HCC, which attributes to 85% of HCC cases in China. The two teams bring complementary expertise required for a successful proteogenomic study of HCC. The China team has already generated the most comprehensive multi-omics dataset yet produced for liver cancer by applying proteogenomic profiling to a Chinese HBV+ HCC cohort (CHCC-HBV) with 159 cases, and the data has been preliminarily analyzed through collaborative efforts between the two teams. In this application, the US team will perform deep computational analyses of the proteogenomics data to generate prognostic models and therapeutic hypotheses, which will be experimentally validated in cell lines, animal models, and clinical specimens by the China team. Our specific Aims are: Aim 1) To develop and validate a protein-based prognostic model; Aim 2) To identify and validate subtype-specific causal drivers and therapeutic strategies; and Aim 3) To characterize the immune landscape of HBV+ HCC. Successful completion of this project will lead to new knowledge on HCC biology as well as new prognostic and treatment strategies for HBV+ HCC. Meanwhile, experimentally validated computational methods developed in this project will have wide application to the study of other cancers and other non-cancer diseases.