Large-Scale Genetic Analyses of Human Cancer

人类癌症的大规模基因分析

• 批准号: 10266043
• 负责人: Valsamo Anagnostou
• 金额: $ 31.11万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266043
• 关键词: Affect; Amino Acid Sequence; Antigens; Autologous; Binding; Biological Assay; Cancer Etiology; Cancer Patient; Candidate Disease Gene; Cell Culture Techniques; Cells; Clinical; Clonality; Code; Colorectal Cancer; Complex; Cytotoxic T-Lymphocytes; DNA Sequence Alteration; Data; Development; Diagnostic; Disease Progression; Equilibrium; Evolution; Funding; Future; Gene Expression; Genes; Genetic; Genomics; Grant; Head Cancer; Histocompatibility Antigens Class I; Human; Immune; Immune Targeting; Immune checkpoint inhibitor; Immune response; Immune system; Immunologics; Immunotherapy; Individual; Intervention; Knowledge; Large-Scale Sequencing; Lead; Link; Liquid substance; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Measures; Mediating; Methods; Molecular; Monitor; Mutation; Neck Cancer; Outcome; Pathway interactions; Patient Selection; Patients; Protein Sequence Analysis; Research Project Grants; Resistance; Resistance development; Somatic Mutation; T cell response; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Therapeutic; Therapeutic Intervention; Time; Translating; Work; anti-tumor immune response; cancer genome; cancer genomics; combinatorial; detection method; exome sequencing; genetic analysis; genome-wide analysis; immune checkpoint blockade; immunogenic; improved; insight; liquid biopsy; malignant breast neoplasm; neoantigens; novel; novel strategies; patient response; predicting response; predictive test; pressure; response; response biomarker; success; targeted agent; targeted treatment; therapy development; therapy outcome; therapy resistant; treatment strategy; tumor; tumor DNA; tumor exome; tumor progression; tumorigenesis

PROJECT SUMMARY Human cancers are caused by the accumulation of mutations in specific genes. During the previous funding periods, our group was the first to determine the sequence of protein coding genes in human cancer and extended this approach to many tumor types. Through this work, we were able to identify candidate genes which had not been previously linked to tumorigenesis, define the basic genomic and neoantigen landscape of common human cancers, and point to pathways that underlie the complex genetic alterations in individual tumor types. More recently, we have identified genomic alterations that are important in the sensitivity and resistance of common targeted therapies as well as immunotherapy. We have pioneered the development of non-invasive circulating tumor DNA approaches to detect and monitor tumors, and have shown that these may be broadly applicable to many cancer patients. These analyses provided new insights into the mechanisms underlying tumorigenesis and have delineated novel avenues for clinical intervention. The recent intersection of cancer genomics with novel immunologic approaches is promising to revolutionize cancer therapeutics. Immune checkpoint inhibitors have demonstrated notable clinical benefit in a variety of tumor types and it is thought that these therapies exert their effects in large part through the immune recognition of mutation associated neoantigens encoded in the genomes of cancer cells. Unfortunately, despite initial successes, a large fraction of patients do not benefit from these treatments or develop resistance after an initial response. Our preliminary data suggest that clinical outcome to immune checkpoint blockade may be determined by the evolving genomic and neoantigen landscape in cancer and that dynamics of the T cell receptor repertoire may be a useful measure of therapeutic outcome. The purpose of this competitive renewal application is to extend our large-scale sequencing efforts to focus on understanding how the evolving genomic and immune landscapes regulate response and resistance to immune checkpoint blockade. First, we propose genome-wide analyses of tumors to examine cancer genome changes under the selective pressure of these therapies. We will develop and utilize computational approaches to predict mutation-associated neoantigens and functionally validate these through novel approaches in patient-specific T cell cultures. Finally, we will develop non-invasive approaches involving circulating tumor DNA and the T cell receptor repertoire to dynamically measure response and resistance to immune checkpoint blockade. The knowledge gained from the studies described in this application will help to broaden our understanding of the underlying mechanisms of response and resistance to immunotherapy. We envision that these analyses will be rapidly translated into the clinical setting, providing new approaches for predicting patient response to current immune-targeted therapies and for development of new treatment strategies.

项目摘要 人类癌症是由特定基因突变的积累引起的。在上一个 资金期，我们的小组是第一个确定人类癌症中蛋白质编码基因序列的人 并将这种方法扩展到许多肿瘤类型。通过这项工作，我们能够识别候选基因 以前尚未与肿瘤发生有关，定义基本基因组和新抗原景观 普通人类癌症，并指出了个体中复杂遗传改变的途径 肿瘤类型。最近，我们确定了在灵敏度和 普通靶向疗法以及免疫疗法的抗性。我们开创了 非侵入性循环肿瘤DNA检测和监测肿瘤的方法，并表明这些方法 可能广泛适用于许多癌症患者。这些分析为您提供了新的见解 肿瘤发生的基础机制，并描绘了用于临床干预的新型途径。 癌症基因组学与新型免疫学方法的最新交集有望 彻底改变了癌症治疗学。免疫检查点抑制剂在 各种肿瘤类型，人们认为这些疗法在很大程度上发挥了作用 对突变的免疫识别与癌细胞基因组中编码的新抗原有关。 不幸的是，尽管最初取得了成功，但很大一部分患者并未从这些治疗中受益或 初始响应后产生阻力。我们的初步数据表明临床结果至免疫 检查点封锁可以通过癌症和新抗原景观不断发展的基因组和新抗原景观确定 T细胞受体库的动力学可能是治疗结果的有用度量。目的 这种竞争性更新的应用程序是扩展我们的大规模测序工作，以关注 了解不断发展的基因组和免疫景观如何调节反应和抵抗力 免疫检查点封锁。首先，我们建议对肿瘤的全基因组分析进行检查。 在这些疗法的选择性压力下变化。我们将开发和利用计算 预测突变相关的新抗原并通过新颖的方法来验证它们的方法 患者特异性T细胞培养物的方法。最后，我们将开发涉及的非侵入性方法 循环肿瘤DNA和T细胞受体库，以动态测量对 免疫检查点封锁。从本申请中描述的研究中获得的知识将有助于 为了扩大我们对反应和免疫疗法抵抗力的潜在机制的理解。 我们设想这些分析将迅速转化为临床环境，提供新的方法 用于预测患者对当前免疫靶向疗法的反应并开发新疗法 策略。