Understanding the Role of HAART in the Progression of HPV-Associated Oral Cancer

了解 HAART 在 HPV 相关口腔癌进展中的作用

• 批准号: 10659250
• 负责人: Craig M Meyers
• 金额: $ 53.62万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-11 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659250
• 关键词: AIDS diagnosis; Affect; Area; Biological Markers; Cancer Burden; Cessation of life; Clinical; Coupled; Development; Disease-Free Survival; Epithelial Cells; Exhibits; General Population; Glycolysis; HIV; HPV-negative head and neck cancer; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Highly Active Antiretroviral Therapy; Human; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; In Vitro; Incidence; Individual; Infection; Life Cycle Stages; Life Expectancy; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Metabolic Pathway; Mitochondria; Modeling; Morbidity - disease rate; Natural History; Oropharyngeal; Patients; Persons; Pharyngeal structure; Positioning Attribute; Prognosis; Radio; Recording of previous events; Recurrence; Respiration; Risk; Role; Sampling; Sampling Studies; Site; Testing; Tissue Sample; Tobacco; Woman; cancer risk; carcinogenicity; chemotherapy; co-infection; cofactor; high risk; improved; malignant mouth neoplasm; malignant oropharynx neoplasm; men; mortality risk; oral HPV infection; oral HPV-positive head and neck cancers; oral cavity epithelium; oral tissue; premalignant; response; scale up; therapeutic target; trend; tumor progression

SUMMARY The overall incidence of HPV+ head and neck squamous cell carcinoma (HNSCC) has exhibited an increasing trend over the last few decades, and has now in the U.S. overtaken cervical cancer as the most common site of HPV related cancer. The majority of patients present with advanced-stage HNSCC are without a clinical history of pre-malignancy. Because there is a paucity of pre-cancer clinical samples the studying the steps of cancer progression that would provide an understanding of the carcinogenic we have developed an in vitro progression model. Interestingly, HPV+ patients compared to HPV negative (HPV-) patients have an improved overall prognosis and greater disease-free survival, attributed partly to a better response to radio- and/or chemotherapy. The mechanisms and natural history of oral HPV infection and carcinogenic progression are poorly understood. Men and women infected with human immunodeficiency virus (HIV) have higher rates of HPV16 infection, longer persistence of HPV16, increased incidence of HNSCC, poorer prognosis, as well as more recurrences after definitive therapy. There have been substantial changes in the burden of cancer affecting HIV-infected individuals in the U.S. during the period spanning the introduction of highly active anti- retroviral therapy (HAART). Scaling-up of HAART therapy has dramatically increased the life expectancy of people living with HIV (PLHIV). As a result of these temporal changes, non-AIDS-defining cancers have come to comprise the majority of cancers in HIV-infected persons during the HAART era. Among these emerging malignancies, HPV-associated cancers of the oral cavity/pharynx increased significantly following an AIDS diagnosis. Most patients with HIV/HPV co-infections on HAART therapy have reduced risk of developing HPV-associated cancers such as cervical cancer but have a higher risk of developing HPV-associated oral cancers the risk is suggested to be due to longer life expectancy as a results of HAART therapy. But it is unclear why HAART therapy may have different effects on HPV+ HNCSCC versus HPV+ cervical cancers. Our overarching hypothesis is that HAART therapy affects the progression of HPV+ HNC. This increases the numbers of PLHIV who have persistent oral HPV infections that progress to HNCSCC, poorer prognosis, and death. We propose to focus on three areas to test this hypothesis. Specific Aim 1. Analyze HAART induced differences of HPV carcinogenic propensity in oral epithelial cells. Specific Aim 2: Investigate the effect of HAART on carcinogenic markers and metabolic pathways associated with HPV+ HNSCC. Specific Aim 3: Study the effect of HAART on glycolysis versus mitochondrial respiration.

概括 HPV+ 头颈鳞状细胞癌 (HNSCC) 的总体发病率呈上升趋势 过去几十年来的趋势，现在在美国已超过宫颈癌，成为最常见的癌症部位 HPV 相关癌症。大多数晚期 HNSCC 患者没有临床病史 属于癌前病变。由于缺乏癌前临床样本，研究癌症的步骤 进展可以帮助我们了解致癌性，我们已经开发了体外进展 模型。有趣的是，与 HPV 阴性 (HPV-) 患者相比，HPV+ 患者的总体情况有所改善 预后和更高的无病生存率，部分归因于对放疗和/或化疗的更好反应。 口腔 HPV 感染和致癌进展的机制和自然史尚不清楚。 感染人类免疫缺陷病毒 (HIV) 的男性和女性的 HPV16 感染率较高 感染、HPV16 持续时间较长、HNSCC 发病率增加、预后较差以及 根治性治疗后复发较多。癌症负担发生了实质性变化 在引入高活性抗病毒药物期间影响了美国的艾滋病毒感染者 逆转录病毒治疗（HAART）。 HAART 治疗的推广极大地延长了患者的预期寿命 艾滋病毒感染者（PLHIV）。由于这些暂时的变化，非艾滋病定义的癌症已经出现 包括 HAART 时代 HIV 感染者的大多数癌症。在这些新兴的 恶性肿瘤、与 HPV 相关的口腔/咽部癌症在 艾滋病诊断。大多数 HIV/HPV 合并感染患者接受 HAART 治疗后，患上 HIV/HPV 的风险降低了。 HPV 相关癌症，如宫颈癌，但患 HPV 相关口腔癌的风险较高 癌症风险被认为是由于 HAART 治疗导致预期寿命延长所致。但尚不清楚 为什么 HAART 治疗对 HPV+ HNCSCC 与 HPV+ 宫颈癌可能有不同的效果。 我们的首要假设是 HAART 治疗会影响 HPV+ HNC 的进展。这增加了 持续口腔 HPV 感染并进展为 HNCSCC 的 PLHIV 人数，预后较差， 和死亡。我们建议重点关注三个领域来检验这一假设。 具体目的1.分析HAART诱导的口腔上皮HPV致癌倾向的差异 细胞。具体目标2：研究HAART对致癌标志物和代谢途径的影响 与 HPV+ HNSCC 相关。具体目标 3：研究 HAART 对糖酵解的影响与 线粒体呼吸。