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: 10528540
• 负责人: Craig M Meyers
• 金额: $ 55.58万
• 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/10528540
• 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 cavity epithelium; oral tissue; 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.

摘要 HPV阳性头颈部鳞状细胞癌(HNSCC)的总发病率呈上升趋势。 过去几十年的趋势，现在在美国已经超过宫颈癌成为最常见的癌症部位 人乳头瘤病毒相关癌症。大多数晚期HNSCC患者都没有临床病史。 有癌症前期的症状。由于癌前临床标本的缺乏，研究癌症的步骤 我们已经开发出了一种体外进展，这将提供对致癌物质的理解 模特。有趣的是，与HPV阴性(HPV-)患者相比，HPV阳性患者的总体改善 预后和更大的无病存活率，部分归因于对放射和/或化疗的更好反应。 口腔HPV感染和致癌进展的机制和自然病史尚不清楚。 感染人类免疫缺陷病毒(HIV)的男性和女性感染HPV16的几率更高 感染、HPV16持续时间较长、HNSCC发病率增加、预后较差以及 在明确治疗后更多的复发。癌症的负担发生了实质性的变化 在推出高效抗病毒药物期间对美国艾滋病毒感染者的影响 逆转录病毒疗法(HAART)。HAART治疗的扩大显著延长了患者的预期寿命 艾滋病毒携带者(PLHIV)。作为这些时间变化的结果，非艾滋病定义的癌症已经出现 在HAART时代，艾滋病毒感染者的癌症占大多数。在这些新兴的国家中 恶性肿瘤，HPV相关的口腔/咽部癌症显著增加后 艾滋病诊断。接受HAART治疗的大多数HIV/HPV混合感染患者降低了发病风险 HPV相关癌症，如宫颈癌，但患HPV相关口腔疾病的风险更高 癌症这种风险被认为是由于HAART治疗导致的预期寿命延长。但目前还不清楚 为什么HAART治疗对HPV+HNCSCC和HPV+宫颈癌的疗效不同。 我们的主要假设是，HAART治疗影响HPV+HNC的进展。这增加了 持续口腔HPV感染进展为HNCSCC的PLHIV患者的数量，预后较差， 和死亡。我们建议集中在三个方面来检验这一假说。 具体目的1.分析HAART诱导口腔上皮细胞HPV致癌倾向的差异 细胞。特定目的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 线粒体呼吸作用。