Prevention of anal cancer in People Living with HIV (PLWH)

预防艾滋病毒感染者 (PLWH) 的肛门癌

• 批准号: 10512062
• 负责人: Evie CARCHMAN
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512062
• 关键词: 3-Dimensional; Adult; Advanced Development; Affect; Anal Intraepithelial Neoplasia; Anal carcinoma; Anus; Autophagocytosis; Back; Biological Assay; CD4 Positive T Lymphocytes; Carcinoma; Caring; Cell Culture Techniques; Cell Line; Cell Survival; Cells; Cervical dysplasia; Clinic; Clinical; Clinical Research; Collaborations; Data; Development; Diagnosis; Disease; Drug Screening; Drug Targeting; Dysplasia; Epithelium; FRAP1 gene; Functional disorder; Goals; Green Fluorescent Proteins; HIV; HIV Infections; HIV Protease Inhibitors; HIV Seronegativity; HIV Seropositivity; HIV-1 protease; HIV/AIDS; Healthcare Systems; Human; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Immune response; Immune system; Immunologic Stimulation; Incidence; Knowledge; Laboratories; Laboratory Study; Lesion; Link; Lopinavir/Ritonavir; Malignant Neoplasms; Malignant neoplasm of anus; Mediating; Methodology; Modeling; Molecular; Oncoproteins; PIK3CG gene; Pathway interactions; Patients; Peripheral; Persons; Population; Positioning Attribute; Pre-Clinical Model; Prevention; Process; Property; Protease Inhibitor; Proteome; Recurrence; Research; Risk; Risk Factors; Serotyping; Sexual Transmission; Squamous cell carcinoma; Study models; T-Cell Depletion; TP53 gene; Testing; Therapeutic; Therapeutic Agents; Tissues; Topical agent; Topical application; Transgenic Mice; Transgenic Model; United States; United States Department of Veterans Affairs; Universities; Veterans; Viral; Wisconsin; Work; anti-cancer; carcinogenesis; chronic infection; effective therapy; efficacy evaluation; high risk; high risk population; human model; immunoregulation; innovation; molecular targeted therapies; mortality; mouse model; multicatalytic endopeptidase complex; novel; novel therapeutic intervention; novel therapeutics; patient population; pharmacologic; pre-clinical; preclinical study; premalignant; prevent; side effect; therapeutic evaluation; therapeutically effective; transcriptome

The incidence of anal cancer, which is largely caused by sexually transmitted human papillomaviruses (HPVs), has been increasing for many years, especially in people living with human immunodeficiency viruses (HIV+). The Department of Veterans Affairs cares for the largest population of people living with human immunodeficiency virus of any healthcare system in the nation. One opportunity for preventing this deadly cancer lies in the effective treatment of precancerous anal intraepithelial neoplasia (hereafter referred to as anal dysplasia). Unfortunately, current treatments for anal dysplasia are ineffective, with high recurrence rates and unwanted, long-term side effects. Dr. Carchman’s laboratory studies anal carcinogenesis in a well- validated, HPV-transgenic model. Through collaborations Dr. Carchman also has access to a new conditional transgenic mouse model to study anal carcinogenesis to facilitate mechanistic studies and test therapeutic agents. Dr. Carchman has identified autophagic dysfunction due to HPV16 E6 and E7 expression that results in anal cancer development. Dr. Sherer’s laboratory has determined that HIV-1 protease inhibitors result in the degradation of HPV E6 and E7, which prevent the destruction of p53, a potent inducer of autophagy. These findings have led the team to pursue preclinical studies that re-purpose HIV protease inhibitors—previously an integral part of HIV treatment—in a topical form to treat anal dysplasia and prevent cancer development. While protease inhibitors have been shown to induce autophagy in several preclinical and clinical studies, they have not been examined in anal dysplasia treatment. The overall hypothesis is that autophagic induction with topical protease inhibitors will prevent the progression of anal dysplasia in preclinical models of anal carcinogenesis, thus providing an effective therapeutic option to prevent HPV-associated anal cancer in humans. The goal of this proposal is to utilize novel preclinical models of HIV-associated anal carcinogenesis, which include a single-cell culture where E6 and E7 are green fluorescent protein (GFP) tagged, an established HPV-transgenic model, and a conditional HPV transgenic model that will undergo immune modulation to recapitulate HIV infection. The team is uniquely positioned to carry out this proposed study. Dr. Carchman has clinical expertise in anal dysplasia and anal cancer and is the leader of the anal dysplasia/cancer clinic at the University of Wisconsin-Madison. The group also has extensive expertise with preclinical models for anal carcinogenesis. These models recently yielded the key observation that autophagy is important for inhibiting anal carcinogenesis—a discovery that drives the proposal’s central premise that HIV protease inhibitors, known to induce autophagy, can be re-purposed as topical agents to prevent anal cancer. The team’s work brings a cancer-relevant problem in the context of an HIV infection back into focus. This research is well-grounded in existing methodology, supported by preliminary data, and holds promise for new treatments to prevent HPV-associated cancers. The project will also advance the development of innovative preclinical models for studying anal carcinogenesis and testing new therapies.

肛门癌的事件主要是由性传播的人乳头瘤病毒（HPV）引起的 多年来已经增加了，尤其是在患有人类免疫缺陷病毒（HIV+）的人们中。 退伍军人事务部关心人口最多的人口 全国任何医疗保健系统的免疫缺陷病毒。防止这种致命的一个机会 癌症在于有效治疗癌前肛门内部肿瘤（以下称为 肛门发育不良）。不幸的是，肛门发育不良的当前治疗方法无效，复发率高 和不需要的长期副作用。 Carchman博士的实验室研究肛门癌变 经过验证的HPV转基因模型。通过合作，Carchman博士还可以使用新的条件 转基因小鼠模型研究肛门癌变，以促进机理研究和测试治疗 代理商。 Carchman博士已经确定了由于HPV16 E6和E7表达而导致的自噬功能障碍 在肛门癌发展中。 Sherer博士的实验室已经确定HIV-1蛋白酶抑制剂导致 HPV E6和E7的降解，可防止p53的破坏，这是一种潜在的自噬诱导剂。这些 调查结果使团队进行了重新使用HIV蛋白酶抑制剂的临床前研究 艾滋病毒治疗的整体部分 - 一种局部治疗肛门发育不良并预防癌症发展的形式。尽管 蛋白酶抑制剂已显示在几项临床前和临床研究中诱导自噬，它们具有 未在肛门发育不良治疗中检查。总体假设是自噬诱导 局部蛋白抑制剂将防止肛门临床前模型中肛门发育不良的进展 癌变，因此提供了一种有效的治疗选择，以防止HPV相关的肛门癌 人类。该提案的目的是利用与HIV相关的肛门癌变的新型临床前模型， 其中包括单细胞培养物，其中E6和E7标记为绿色荧光蛋白（GFP） 已建立的HPV转基因模型和有条件的HPV转基因模型，该模型将接受免疫 调节以概括HIV感染。该团队的独特位置可以进行这项拟议的研究。博士 Carchman在肛门发育不良和肛门癌方面具有临床专业知识，是肛门的领导者 威斯康星大学麦迪逊分校的发育不良/癌症诊所。该小组还拥有广泛的专业知识 肛门癌变的临床前模型。这些模型最近得出了一个自噬的关键观察 对于抑制肛门癌变非常重要，这一发现驱动了该提议的中心前提，即艾滋病毒 可以将蛋白酶抑制剂（已知会诱导自噬诱导的蛋白酶抑制剂）重新塑造为局部剂，以预防肛门癌。 在艾滋病毒感染的背景下，该团队的工作带来了与癌症相关的问题。这 研究在现有方法中占据了良好的基础，在初步数据的支持下，对新的有希望 治疗以防止HPV相关的癌症。该项目还将推动创新的发展 用于研究肛门癌变和测试新疗法的临床前模型。