Role of FAT1 somatic mutations in aggressiveness of head and neck cancer

FAT1体细胞突变在头颈癌侵袭性中的作用

• 批准号: 10669277
• 负责人: Zhengjia Chen
• 金额: $ 15.88万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669277
• 关键词: Adhesions; Affect; Aggressive behavior; Antibodies; Applications Grants; Bioinformatics; Biological; Biological Assay; Biological Markers; Biometry; Blocking Antibodies; Categories; Cell Polarity; Cell physiology; Cell surface; Cells; Cetuximab; Characteristics; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; Data; Data Set; Databases; Development; Disease Progression; ERBB3 gene; Epidermal Growth Factor Receptor; Exhibits; FAT gene; Gene Expression; Gene Mutation; Genes; Genetic; Genomics; Goals; Growth; Growth Factor; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human Papillomavirus; Immune; Immune checkpoint inhibitor; KDR gene; Knock-out; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Mediating; Molecular; Mutate; Mutation; National Institute of Dental and Craniofacial Research; Nature; Neoplasm Metastasis; Newly Diagnosed; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Phase; Process; Prognosis; Prognostic Marker; Protein Array; Proteins; Proteomics; Publications; Published Database; Publishing; Recurrence; Reporting; Research Project Grants; Resistance; Role; Signal Pathway; Somatic Mutation; Testing; The Cancer Genome Atlas; Tumor Promotion; Tumor Suppressor Proteins; United States National Institutes of Health; Validation; angiogenesis; bioinformatics tool; candidate marker; cell motility; exome sequencing; gene product; genetic regulatory protein; genomic data; immunoregulation; improved; improved outcome; in vitro Bioassay; melanoma; mouse model; mutant; potential biomarker; programmed cell death protein 1; protein expression; response; targeted treatment; transcriptome sequencing; treatment strategy; tumor; tumor heterogeneity; tumor microenvironment; tumorigenesis

PROJECT SUMMARY This proposed R03 application responds to NIDCR PAR-20-046 announcement entitled “NIDCR Small Research Grants for Analyses of Existing Genomics Data”. The project aims to identify significantly altered protein and gene mutation, expression, signaling pathways, and immune regulatory networks mediated by or associated with FAT1 mutations, which contribute to aggressiveness of head and neck squamous cell carcinoma (HNSCC). We will use existing genomic and proteomic data from The Cancer Genome Atlas (TCGA), NCI’s Clinical Proteomic Tumor Analysis Consortium (CPTAC), and other published databases to perform bioinformatics and biostatistics analyses. The major functional impacts of identified molecules will be confirmed by appropriate biological assays, ranked as potential biomarker candidates which will be validated using datasets with patient clinical outcome. Recently, TCGA study reported a FAT1 mutation rate of 23% in HNSCC, which was higher in human papilloma virus (HPV)-negative cancer. Wild-type FAT1 exhibits a tumor suppressor activity, and the majority of mutated FAT1 genes are inactivated by missense or truncation, leading to altered or terminated gene products. However, the role of FAT1 mutants in HNSCC oncogenesis and progression remain poorly understood. We and others observed that FAT1 mutations were potentially correlated with response to a combination therapy with cetuximab and CDX-3379 (a HER3 blocking antibody) in a phase I HNSCC clinical trial. Although both EGFR targeted therapy and immune checkpoint inhibitors (ICIs) have improved HNSCC patients’ outcome, most patients either do not benefit or have disease progression on these therapies. We hypothesize that FAT1 mutations may modulate key molecules involved in growth, metastasis, angiogenesis, and immunomodulation, which contribute to resistance to targeted therapies and ICIs and affect the prognosis of HNSCC. To support this hypothesis, we have used TCGA genomics and proteomics databases and identified associations between FAT1 mutations and altered protein expressions, with potential implications in modulation of cellular sensitivity to EGFR targeted therapy and ICIs, cancer metastasis/angiogenesis, and immune regulatory proteins in the HNSCC micro-environment. In this project, we propose two aims to test this hypothesis with a focus on FAT1 truncated/deletion mutants. Aim 1: To understand genomic, proteomic, and mechanistic functions of FAT1 mutations and their associated signaling pathways that regulate responses to targeted therapies and ICIs and enhance metastasis/recurrence potential; Aim 2: To discover FAT1 mutation-associated biomarkers that are correlated with sensitivity to targeted therapies of EGFR/HER3, VEGFR2, and ICIs and affect the prognosis of HNSCC patients. At the conclusion of this project, we expect to provide strong evidence to support the role of FAT1 mutations and associated pathways in promoting HNSCC progression. These data will be used for the development of a major grant application, such as an NIH R01, to elucidate the functional mechanisms of this prevalent mutation and develop new diagnosis or treatment strategies for HNSCC patients.

项目摘要 此建议的R 03应用程序响应NIDCR PAR-20-046公告，标题为“NIDCR小型研究 现有基因组学数据分析赠款”。该项目旨在识别显著改变的蛋白质， 基因突变、表达、信号通路和免疫调节网络介导或相关 FAT 1突变，导致头颈部鳞状细胞癌（HNSCC）的侵袭性。我们 将使用现有的基因组和蛋白质组数据从癌症基因组图谱（TCGA），NCI的临床蛋白质组学 肿瘤分析联盟（CPTAC）和其他已发表的数据库进行生物信息学和生物统计学 分析。已鉴定分子的主要功能影响将通过适当的生物学测定来确认， 被列为潜在的生物标志物候选者，将使用具有患者临床结果的数据集进行验证。 最近，TCGA研究报告HNSCC中的FAT 1突变率为23%，在人乳头状瘤中更高 HPV阴性的癌症。野生型FAT 1表现出肿瘤抑制活性，并且大多数突变的FAT 1具有肿瘤抑制活性。 FAT 1基因因错义或截短而失活，导致基因产物改变或终止。然而，在这方面， FAT 1突变体在HNSCC肿瘤发生和发展中的作用仍然知之甚少。我们和其他人 观察到FAT 1突变可能与西妥昔单抗联合治疗的反应相关 和CDX-3379（一种HER 3阻断抗体）在I期HNSCC临床试验中的应用。尽管EGFR靶向 治疗和免疫检查点抑制剂（ICI）改善了HNSCC患者的结局，大多数患者 对这些治疗没有益处或有疾病进展。我们假设FAT 1突变可能 调节参与生长、转移、血管生成和免疫调节的关键分子， 导致对靶向治疗和ICI的耐药性，并影响HNSCC的预后。支持 基于这一假设，我们使用了TCGA基因组学和蛋白质组学数据库， FAT 1突变和改变的蛋白质表达，在细胞敏感性调节中具有潜在意义 EGFR靶向治疗和ICI，癌症转移/血管生成和免疫调节蛋白， HNSCC微环境。在这个项目中，我们提出了两个目标来测试这个假设，重点是FAT 1 截短/缺失突变体。目的1：了解FAT 1的基因组学、蛋白质组学和机制功能 调节靶向治疗和ICI反应的突变及其相关信号通路， 增强转移/复发潜力;目的2：发现FAT 1突变相关的生物标志物， 与EGFR/HER 3、VEGFR 2和ICI靶向治疗的敏感性相关，并影响 HNSCC患者。在这个项目结束时，我们希望提供强有力的证据来支持的作用， FAT 1突变和相关途径促进HNSCC进展。这些数据将用于 开发一个主要的赠款申请，如NIH R 01，以阐明这一功能机制， 流行的突变，并为HNSCC患者开发新的诊断或治疗策略。