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: 10510325
• 负责人: Zhengjia Chen
• 金额: $ 16.92万
• 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/10510325
• 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; Diagnosis; 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; In Vitro; KDR gene; Knock-out; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Mediating; Molecular; Mutate; Mutation; National Institute of Dental and Craniofacial Research; Neoplasm Metastasis; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Phase; Play; 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 Suppressor Proteins; Tumor-infiltrating immune cells; United States National Institutes of Health; Validation; angiogenesis; base; bioinformatics tool; candidate marker; cell motility; exome sequencing; gene product; genetic regulatory protein; genomic data; immunoregulation; improved; improved outcome; 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 该提出的R03申请响应NIDCR PAR-20-046公告标题为“ NIDCR小型研究 该项目旨在确定蛋白质和 基因突变，表达，信号通路和免疫调节网络由或与之相关 FAT1突变有助于头颈鳞状细胞癌（HNSCC）的侵略性。我们 将使用来自癌症基因组图集（TCGA）的现有基因组和蛋白质组学数据，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，以执行生物信息学和生物统计学 分析。鉴定分子的主要功能影响将通过适当的生物学测定确认， 被评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研究报告了HNSCC的FAT1突变率为23％，在人类乳头瘤中较高。 病毒（HPV）阴性癌。野生型FAT1表现出肿瘤抑制活性，大多数突变 FAT1基因被错义或截断灭活，导致或终止基因产物改变。然而， FAT1突变体在HNSCC造成生成和进展中的作用仍然很少了解。我们和其他人 观察到脂肪1突变可能与对西妥昔单抗组合疗法的反应有可能相关 在I期HNSCC临床试验中，和CDX-3379（一种HER3阻断抗体）。尽管两个EGFR都针对 治疗和免疫检查点抑制剂（ICI）有改善的HNSCC患者的结果，大多数患者既可以 在这些疗法上不要受益或疾病进展。我们假设FAT1突变可能 调节与生长，转移，血管生成和免疫调节有关的关键分子，这 有助于对靶向疗法和ICIS的抗性，并影响HNSCC的预后。支持 这个假设，我们使用了TCGA基因组学和蛋白质组学数据库，并确定了之间的关联 FAT1突变和蛋白质表达改变，对细胞敏感性的调节有潜在的影响 在EGFR靶向治疗和ICIS，癌症转移/血管生成以及免疫调节蛋白中 HNSCC微环境。在这个项目中，我们提出了两个旨在检验这一假设的目标，重点是FAT1 截短/缺失突变体。目的1：了解FAT1的基因组，蛋白质组学和机械功能 突变及其相关的信号通路，调节对靶向疗法和ICI的反应以及 增强转移/复发潜力；目标2：发现与FAT1突变相关的生物标志物 与对EGFR/HER3，VEGFR2和ICIS的靶向疗法的敏感性相关，并影响预后 HNSCC患者。在该项目的结论下，我们希望提供有力的证据来支持 FAT1突变和促进HNSCC进展的相关途径。这些数据将用于 开发主要的赠款应用程序，例如NIH R01，以阐明其功能机制 普遍的突变并为HNSCC患者制定新的诊断或治疗策略。