Downstream effects of HPV integration on survival/metastasis in oropharyngeal cancer

HPV 整合对口咽癌生存/转移的下游影响

• 批准号: 10438782
• 负责人: Nisha J D'Silva
• 金额: $ 58.46万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10438782
• 关键词: Address; Affect; Age; Alcohol consumption; Animal Model; Automobile Driving; Biological Assay; Biological Markers; Biology; Cell Differentiation process; Cell Line; Cells; Cessation of life; Chick; Clinical Trials; DNA Repair Pathway; Data; Diagnosis; Disease; Distant Metastasis; Epidemic; Epidemiologist; Event; Exhibits; Genes; Genome; Goals; Grant; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Health; Human; Human Papillomavirus; Human papillomavirus 16; Image; Image Analysis; Immune; Immune response; In Vitro; Incidence; Individual; Infection; Length; Life; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Methods; Michigan; Molecular; Mus; Mutation; Neoplasm Metastasis; Oncogenes; Oncogenic; Oropharyngeal; Oropharyngeal Squamous Cell Carcinoma; Oxidation-Reduction; Oxidative Phosphorylation; PIK3CA gene; Pathologist; Patient-Focused Outcomes; Patients; Phase II Clinical Trials; Play; Positioning Attribute; Prevalence; Process; Prognosis; Protein Isoforms; Protocols documentation; Quality of life; RNA Splicing; Race; Recurrence; Regimen; Resources; Risk; Role; Sampling; Selection for Treatments; Signal Pathway; Site; Slide; Smoking; Survival Rate; Survivors; Treatment Protocols; Treatment-related toxicity; Tumor Markers; Tumor Subtype; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Universities; Vaccination; base; cancer diagnosis; cancer imaging; chorioallantoic membrane; cohort; epithelial to mesenchymal transition; high risk; improved; in vivo; in vivo Model; keratinocyte differentiation; malignant oropharynx neoplasm; neoplastic cell; patient subsets; predictive marker; prognostic; radiation resistance; radiation response; sex; therapy resistant; transcriptome sequencing; treatment effect; treatment group; treatment response; tumor; tumor progression; vector

Abstract The incidence of human papillomavirus associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is rising in the US, and is now even more prevalent than cervical cancer. Due to low HPV vaccination rates and the decades long latency period between HPV infection and cancer diagnosis, HPV+ OPSCC remains a major health concern, with the most likely reason for death being distant metastasis. Furthermore, due to the life-long detrimental treatment effects on quality of life for survivors, it is essential to identify a subset of patients who would benefit from de-escalated treatment. Our long term goal is to differentiate HPV+ patients who have a good prognosis and are most likely to benefit from de-escalated therapy and those who require the standard, or a more aggressive regimen. Our group first characterized two main subtypes of HPV+ OPSCC, identifying HPV integration into the host genome as the driving factor in determining tumor subtype. Furthermore, we and others have shown that HPV integration status is associated with overall survival. In this proposal we plan to study three downstream effects of HPV integration identified by our group and others: an increase in the splicing of HPV oncogene E6 to E6*, a decrease in the tumor immune response, and a change in cell differentiation status. Each of these effects plays a role in determining metastasis and survival, however the mechanism of their effect and their relative contributions remain unclear. In aim 1, we will disentangle the above three effects of HPV integration on overall and disease-specific survival using a University of Michigan cohort of 300 patients, and we will compare methods for defining HPV integration status. We will also optimize a biomarker for tumor immune infiltration based on H&E slides. In aim 2, we will examine the oncogenic effects of the shift to expressing the shorter E6* isoform instead of full length E6, using in vitro and in vivo models. This was observed by us and others to increase oxidative phosphorylation and potentially tumor mutational burden. Finally, in aim 3 we will use in vitro and vivo models to examine mechanism by which HPV integration and/or the shift to E6* expression modulate cell invasion and treatment response. Based on our results, we will begin one or more biomarker-based pilot phase II clinical trials.

抽象的 人乳头瘤病毒相关的（HPV+）口咽鳞状细胞癌（OPSCC）的发生率 在美国，正在上升，现在比宫颈癌更普遍。由于HPV疫苗接种率低 HPV感染与癌症诊断之间的数十年延迟期，HPV+ OPSCC仍然是一个 主要的健康问题，最有可能导致死亡的原因是遥远的转移。此外，由于 终身有害治疗对幸存者生活质量的影响，必须确定一部分 将受益于降级治疗的患者。我们的长期目标是区分HPV+患者 他们的预后良好，最有可能从降级疗法中受益，以及那些需要的人 标准或更具侵略性的方案。我们的小组首先表征了HPV+ OPSCC的两个主要子类型， 将HPV整合到宿主基因组中是确定肿瘤亚型的驱动因子。 此外，我们和其他人已经表明，HPV整合状态与总体生存有关。 在此提案中，我们计划研究我们小组确定的HPV集成的三个下游效应， 其他：HPV癌基因E6对E6*的剪接增加，肿瘤免疫反应的降低和 细胞分化状态的变化。这些影响中的每一个都在确定转移和 生存，但是其作用的机制及其相对贡献尚不清楚。在AIM 1中，我们将 使用A删除HPV整合对整体和疾病特异性生存的上述三种影响 密歇根大学队列300名患者，我们将比较定义HPV集成的方法 地位。我们还将优化一种基于H＆E载玻片的肿瘤免疫浸润的生物标志物。在AIM 2中，我们将 使用转移向表达较短的E6*同工型而不是全长E6的致癌作用，使用 体外和体内模型。这是我们和其他人观察到的，以增加氧化磷酸化和 潜在的肿瘤突变负担。最后，在AIM 3中，我们将使用体外和体内模型检查 HPV整合和/或转移到E6*表达的机制调节细胞侵袭和处理 回复。根据我们的结果，我们将开始一个或多个基于生物标志物II期临床试验。