Defining Drivers of HPV-associated Carcinogenesis

摘要 人乳头瘤病毒（HPV）相关的癌症占所有人类癌症的5%，是最常见的癌症之一。 艾滋病毒感染人群中常见的恶性肿瘤。虽然高效的预防性疫苗 尽管如此，在美国的使用率仍然很低。与此同时，HPV相关的癌症，特别是 肛门癌在美国的发病率正在上升，特别是在艾滋病毒感染人群中。 这些癌症的治疗依赖于几十年来使用放射和传统的治疗方法。 化疗剂。在许多情况下，这些治疗是没有治愈性的，有效的治疗选择有限。 二线或三线治疗。我们研究的目标是确定驱动HPV相关性的因素， 癌症发生的最终目标是确定更好地治疗这些癌症患者的方法。这是 特别是对艾滋病毒感染人群的关注，他们患这些癌症的风险越来越大。 我们已经组装了一个独特的模型试剂的工具箱，以解决这一目标，包括遗传 工程小鼠（GEM）模型，以及患者来源的异种移植物（PDX）和相关细胞株 来自肛门癌、宫颈癌和头颈癌患者。我们已经扩大了实验工具箱， 包括MmuPV 1，一种小鼠乳头状瘤病毒，其在发病机制和 分子活动。使用这些模型，我们将探索新的治疗靶点，用于预防和/或 HPV相关疾病/癌症的治疗。特别是与艾滋病毒相关的肿瘤，我们将 使用肛门癌的PDX模型，比较HIV引起的癌症对靶向治疗的反应， 感染与未感染的患者，以了解是否存在潜在临床重要性的差异。的 拟议的研究建立在我们过去2年多来研究GEM和PDX所获得的见解基础上 HPV相关癌症的模型。

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.