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

项目总结 这一建议的R03应用程序响应了NIDCR PAR-20-046的公告，其标题为“NIDCR Small Research 用于分析现有基因组数据的赠款“。该项目旨在识别显著改变的蛋白质和 基因突变、表达、信号通路和由其介导或相关的免疫调节网络 FAT1突变，导致头颈部鳞状细胞癌(HNSCC)的侵袭性。我们 将使用来自癌症基因组图谱(TCGA)的现有基因组和蛋白质组数据，NCI的临床蛋白质组 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。识别出的分子的主要功能影响将通过适当的生物测试来确认， 被列为潜在的生物标记物候选，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中FAT1突变率为23%，在人乳头状瘤中更高 病毒(HPV)阴性的癌症。野生型FAT1显示出肿瘤抑制活性，并且大多数突变 FAT1基因因错义或截断而失活，导致基因产物改变或终止。然而， FAT1突变体在HNSCC发生和发展中的作用仍然知之甚少。我们和其他人 观察到FAT1突变与西妥昔单抗联合治疗的反应潜在相关 和CDX-3379(一种HER3封闭抗体)在HNSCC I期临床试验中。尽管两个EGFR都针对 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 不会受益于这些疗法，也不会使疾病恶化。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，其中 导致对靶向治疗和ICIS的抵抗，并影响HNSCC的预后。支持 这一假设，我们使用了TCGA基因组学和蛋白质组学数据库，并确定了两者之间的关联 FAT1突变和蛋白表达变化在细胞敏感性调节中的潜在意义 到EGFR靶向治疗和ICIS，肿瘤转移/血管生成，以及免疫调节蛋白在 HNSCC的微环境。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 截短/缺失突变体。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ICIS的反应 增强转移/复发潜力；目标2：发现与FAT1突变相关的生物标记物 与EGFR/HER3、VEGFR2和ICIS靶向治疗的敏感性相关，并影响预后 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 促进HNSCC进展的FAT1突变及其相关途径。这些数据将用于 开发一个重要的拨款申请，如NIH R01，以阐明其作用机制 并为HNSCC患者开发新的诊断或治疗策略。

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.