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.

摘要