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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要此拟议的 R03 应用程序响应题为“NIDCR Small Research”的 NIDCR PAR-20-046 公告为现有基因组数据分析提供资助”，该项目旨在显着识别改变的蛋白质和基因组。由其介导或与之相关的基因突变、表达、信号传导途径和免疫调节网络 FAT1 突变，导致头颈鳞状细胞癌 (HNSCC) 的侵袭性。将使用来自 NCI 临床蛋白质组学癌症基因组图谱 (TCGA) 的现有基因组和蛋白质组学数据肿瘤分析联盟 (CPTAC) 和其他已发布的数据库，用于执行生物信息学和生物统计学已识别分子的主要功能影响将通过适当的生物测定来证实，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研究报道HNSCC中FAT1突变率为23%，在人乳头状瘤中更高野生型 FAT1 表现出肿瘤抑制活性，并且大多数突变型。 FAT1 基因因错义或截短而失活，导致基因产物改变或终止。我们和其他人对 FAT1 突变体在 HNSCC 肿瘤发生和进展中的作用仍知之甚少。观察到 FAT1 突变可能与西妥昔单抗联合治疗的反应相关和 CDX-3379（一种 HER3 阻断抗体）正在进行 I 期 HNSCC 临床试验，尽管两者都针对 EGFR。治疗和免疫检查点抑制剂 (ICIs) 改善了 HNSCC 患者的预后，大多数患者要么我们发现 FAT1 突变可能不会使这些疗法受益或导致疾病进展。调节参与生长、转移、血管生成和免疫调节的关键分子，有助于对靶向治疗和 ICI 产生耐药性并影响 HNSCC 的预后。针对这一假设，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具有潜在影响 EGFR 靶向治疗和 ICI、癌症转移/血管生成以及免疫调节蛋白在这个项目中，我们提出了两个目标来检验这一假设，重点是 FAT1。目的 1：了解 FAT1 的基因组、蛋白质组和机制功能。突变及其相关信号通路调节对靶向治疗和 ICI 的反应，增强转移/复发潜力；目标 2：发现 FAT1 突变相关的生物标志物与 EGFR/HER3、VEGFR2 和 ICI 靶向治疗的敏感性相关，并影响预后在该项目结束时，我们希望提供强有力的证据来支持 HNSCC 患者的作用。 FAT1 突变和促进 HNSCC 进展的相关途径这些数据将用于研究。开发一项重大资助申请，例如 NIH R01，以阐明其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。