Dissecting NF-kB pathway in HPV-associated head and neck cancer

剖析 HPV 相关头颈癌中的 NF-kB 通路

• 批准号: 10660309
• 负责人: Natalia Issaeva
• 金额: $ 48.87万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660309
• 关键词: Automobile Driving; Bioinformatics; Biological Markers; CD4 Positive T Lymphocytes; Cancer Etiology; Cell Proliferation; Cells; Characteristics; Classification; Clinical Trials; Coupled; Cytoprotection; Data; Defect; Deglutition; Disease; Down-Regulation; Engineering; Epidemic; Episome; Etiology; Functional disorder; Gene Expression; Genes; Goals; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papillomavirus 16; In complete remission; Incidence; Infiltration; Maintenance; Mediating; Modeling; Morbidity - disease rate; Mutation; NF-kappa B; Oncology; Oxidative Stress; Papillomavirus Transforming Protein E6; Pathway Analysis; Pathway interactions; Patients; Pattern; Prognosis; Prognostic Marker; Quality of life; Radiation; Radiation Tolerance; Radiation therapy; Recurrence; Recurrent tumor; Reporting; Risk; Role; Signal Transduction; Speech; Survivors; TNF receptor-associated factor 3; Testing; Therapeutic; Tobacco; Treatment Failure; Viral Genes; Work; anti-tumor immune response; biological adaptation to stress; carcinogenesis; cervical and uterine cancer; chemotherapy; cohort; effective therapy; high risk; human papilloma virus oncogene; immune cell infiltrate; improved; metaplastic cell transformation; novel therapeutics; oral HPV-positive head and neck cancers; personalized cancer care; promoter; protective pathway; response; side effect; survival prediction; treatment response; tumor; tumor microenvironment; tumorigenesis

Project summary The incidence of HPV-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) has dramatically increased over the last few decades and continues to rise. Despite the magnitude of this epidemic, mechanisms of HPV-driven carcinogenesis in HPV+ HNSCC have not been thoroughly investigated. Compared to patients with tobacco-associated HNSCC, those with HPV+ HNSCC have increased overall survival and higher response to treatment, which usually consists of chemo- and radiation therapy; however, survivors frequently suffer from treatment’s toxic side effects, such as swallowing and speech dysfunction. In addition, approximately 25% of HPV+ HNSCC patients develop recurrent or metastatic disease, for which there are limited treatment options. A pressing goal in head and neck oncology is to decrease the morbidity of therapy for HPV+ HNSCC through treatment de-escalation. However, biomarkers that identify HPV+ patients with good prognosis, who may be appropriate for de-escalation therapy, are lacking. Using three independent cohorts, we found that constitutively active NF-κB (usually arising from genetic defects in NF-κB regulators, including TRAF3 and CYLD) correlates with survival and should be explored as a prognostic biomarker in HPV+ HNSCC. Our preliminary data suggest that survival benefits of patients, whose tumors harbor overactive NF-κB, are attributed to better tumor response to therapy and that both, inherent NF-κB-driven tumor characteristics (e.g. downregulated expression of oxidative stress response, NRF2 target genes), as well as a distinct tumor microenvironment (e.g. elevated number of tumor infiltrating CD4+ T cells), may contribute to increased sensitivity of NF-κB active tumors to radiation. We previously reported that mutations in TRAF3 and CYLD were associated with a lack of HPV integration, leading us to hypothesize that NF-κB activation may enable cells to maintain HPV episomes. Since the canonical HPV carcinogenesis model depends on HPV integration, we also hypothesize that activation of NF-κB may be critical for an alternative mechanism of HPV carcinogenesis driven by HPV episomal maintenance. To explore our hypothesis, in Specific Aim 1, we will investigate the impact of NF-κB signaling on HPV gene expression and episomal maintenance. In Specific Aim 2, we will explore the significance of NF-κB pathway on cellular proliferation, survival, and cellular transformation in response to HPV. Finally, Specific Aim 3 will explore mechanisms of NF-κB mediated radiation sensitivity in HPV+ HNSCC.

项目摘要 HPV相关（HPV+）头颈鳞状细胞癌（HNSCC）的事件具有 尽管这种流行病的幅度 尚未对HPV+ HNSCC中HPV驱动的癌变的机制进行彻底研究。比较的 对于与烟草相关的HNSCC患者，患有HPV+ HNSCC的患者的总生存率增加，并且 对治疗的反应更高，通常由化学疗法和放射治疗组成；但是，幸存者 经常患有治疗的有毒副作用，例如吞咽和语音功能障碍。此外， 大约25％的HPV+ HNSCC患者出现复发或转移性疾病 治疗选择。头部和颈部肿瘤学的一个紧迫目标是降低治疗HPV+的发病率 HNSCC通过治疗降级。但是，鉴定出良好发病的HPV+患者的生物标志物， 可能缺乏适合降级治疗的人。使用三个独立队列，我们​​发现 组成型活性NF-κB（通常是由NF-κB调节剂中的遗传缺陷引起的，包括TRAF3和CYLD） 与生存相关，应作为HPV+ HNSCC中的预后生物标志物探索。我们的初步 数据表明，肿瘤具有过度活跃的NF-κB的患者的生存益处归因于更好 肿瘤对治疗的反应以及两者固有的NF-κB驱动肿瘤特征（例如下调 氧化应激反应的表达，NRF2靶基因）以及独特的肿瘤微环境（例如 肿瘤浸润的CD4+ T细胞数量升高），可能有助于NF-κB活性的敏感性提高 肿瘤到辐射。我们先前报道说，TRAF3和CYLD中的突变与缺乏 HPV的整合，导致我们假设NF-κB激活可能使细胞保持HPV发作。 由于规范的HPV癌变模型取决于HPV的整合，因此我们还假设激活 NF-κB的of对于由HPV偶发驱动的HPV癌变的替代机制至关重要 维护。为了探讨我们的假设，在特定的目标1中，我们将研究NF-κB信号对 HPV基因表达和偶发性维持。在特定目标2中，我们将探讨NF-κB的意义 响应HPV的细胞增殖，存活和细胞转化的途径。最后，特定的目标 3将探索HPV+ HNSCC中NF-κB介导的辐射灵敏度的机制。