Defining Drivers of HPV-associated Carcinogenesis

摘要 与人类乳头瘤病毒(HPV)相关的癌症占所有人类癌症的5%，是 在艾滋病毒感染人群中出现的常见恶性肿瘤。虽然高效的预防性疫苗是 尽管可用，但它们在美国的利用率仍然很低。与此同时，与HPV相关的癌症，特别是 在美国，肛门癌的患病率正在增加，特别是在感染艾滋病毒的人群中。 这些癌症的治疗依赖于几十年来使用放射和传统方法 化疗药物。在许多情况下，这些治疗方法不能治愈，有效的选择有限。 二线或三线治疗。我们研究的目标是确定驱动HPV相关的因素 癌症的发生，最终目标是确定更好地治疗这些癌症患者的方法。这是 尤其令艾滋病毒感染人群感到关切的是，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工具箱，用来解决这一目标，包括从基因上 工程化小鼠(GEM)模型以及患者来源的异种移植(PDX)和相关细胞株 来自肛门癌、子宫颈癌和头颈癌患者。我们已经将我们的实验工具箱扩大到 包括MmuPV1，一种小鼠乳头状瘤病毒，在其发病机制和 分子活动。利用这些模型，我们将探索新的预防和/或治疗靶点 HPV相关疾病/癌症的治疗。与艾滋病毒相关的肿瘤特别相关，我们将 使用用于肛门癌的PDX模型来比较HIV引起的癌症之间对靶向治疗的反应 了解感染患者与未感染患者是否存在潜在的临床重要性差异。这个 拟议的研究建立在我们过去20多年来对创业板和PDX的研究中获得的见解的基础上 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.