Defining Drivers of HPV-associated Carcinogenesis

定义 HPV 相关癌变的驱动因素

• 批准号: 10457853
• 负责人: PAUL F. LAMBERT
• 金额: $ 91.8万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457853
• 关键词: Address; Anus; Cells; Cervical; Chest; Clinical; Cutaneous; Disease; Genetically Engineered Mouse; Goals; HIV; Head and Neck Cancer; Human; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Individual; Laboratories; Learning; Malignant Neoplasms; Malignant neoplasm of anus; Modeling; Molecular; Mus; Mutation; Neoplasms; Papillomavirus; Pathogenesis; Patients; Population; Prevalence; Prevention; Preventive vaccine; Radiation; Reagent; Research; Risk; United States; cancer therapy; carcinogenesis; chemotherapeutic agent; high risk; insight; new therapeutic target; novel strategies; patient derived xenograft model; response; targeted treatment; tool; vaccine access

ABSTRACT Human papillomavirus (HPV)-associated cancers represent 5% of all human cancers and are among the most common malignancies arising in the HIV-infected population. While highly effective prophylactic vaccines are available, their utilization in the United States remains low. Meanwhile HPV-associated cancers, particularly anal cancer, are increasing in their prevalence here in the US especially among the HIV-infected population. Treatment of these cancers relies upon decades old approaches using radiation and traditional chemotherapeutic agents. In many cases, these treatments are not curative, with limited options for effective second or third line treatments. The goal of our research is to define the factors that drive HPV-associated carcinogenesis with the ultimate goal to define ways to better treat patients with these cancers. This is particularly of concern to the HIV-infected population who are at increasing risk of developing these cancers. We have assembled a tool chest of unique model reagents with which to address this goal including genetically engineered mouse (GEM) models, as well as patient derived xenografts (PDXs) and associated cell strains from patients with anal, cervical and head/neck cancers. We have expanded our experimental tool chest to include MmuPV1, a mouse papillomavirus that models high-risk cutaneous HPVs in both its pathogenesis and molecular activities. Using these models we will explore new therapeutic targets for the prevention and/or treatment of HPV-associated disease/cancers. Of particular relevance to HIV-associated neoplasia, we will use PDX models for anal cancer to compare responses to targeted therapies between cancers arising in HIV- infected versus uninfected patients to learn if there are differences of potential clinical importance. The proposed studies build upon insights we have gained over the past 2+ decades studying our GEM and PDX models for HPV-associated cancers.

抽象的 人乳头瘤病毒（HPV）相关的癌症占所有人类癌症的5％，是最多的癌症 艾滋病毒感染人群引起的常见恶性肿瘤。虽然高效的预防性疫苗是 可用的是，它们在美国的利用率仍然很低。同时，与HPV相关的癌症，特别是 肛门癌在美国的患病率正在增加，尤其是在艾滋病毒感染的人群中。 这些癌症的处理依赖于使用辐射和传统的数十年 化学治疗剂。在许多情况下，这些治疗方法无法治愈，有限的选择有效 第二或第三行处理。我们研究的目的是定义推动HPV相关的因素 致癌作用的最终目标是定义更好地治疗这些癌症患者的方法。这是 尤其是关注感染的艾滋病毒的人群，他们正在增加发展这些癌症的风险。 我们组装了一个独特模型试剂的工具箱，以解决该目标，包括基因 工程小鼠（GEM）模型以及患者衍生的异种移植物（PDX）和相关的细胞菌株 来自患有肛门，宫颈和头部癌症的患者。我们已经将实验工具箱扩展到 包括MMUPV1，一种小鼠乳头瘤病毒，在其发病机理和 分子活动。使用这些模型，我们将探索用于预防和/或 治疗HPV相关疾病/癌症。与艾滋病毒相关的肿瘤特别相关，我们将 使用PDX模型进行肛门癌，比较在HIV中引起的癌症的靶向疗法的反应 感染与未感染的患者学习是否存在潜在临床重要性的差异。这 拟议的研究以我们在过去的20多年中获得的洞察力为基础，研究了我们的宝石和PDX HPV相关癌症的模型。