Strategies Against HPV Related Genital Diseases in Women

人乳头瘤病毒(HPV)是女性下生殖道肿瘤的重要病原体。与其他致癌物的新的相互作用和/或免疫缺陷导致肿瘤的发生和癌症的进展。然而，缺乏足够的动物模型和前瞻性临床试验都是开发有效的抗HPV疗法的障碍，也阻碍了对人类与这种病毒相互作用的彻底了解。这项建议的目的是为了支持Bradley J.Monk医学博士的职业发展。在Luis P.Villarreal博士博士的指导下，Monk博士将在最近描述的一种严重联合免疫缺陷小鼠模型中评估共致癌物质和抗病毒药物，该模型使用植入型人HPV感染的上皮细胞，宫颈上皮内瘤变(CIN)。蒙克博士建议研究这些颈部组织植入物的肿瘤性转化以及进展或退化。将研究特定启动子或遗传毒性化合物(如激素、尼古丁)以及新型抗HPV药物(如刺激免疫细胞、反义癌基因)和营养补充剂(如吲哚3-甲醇或I3C)的影响。此外，在妇科肿瘤学家菲利普·J·迪萨亚医学博士、擅长化学预防的医学肿瘤学家弗兰克·L·迈斯肯斯医学博士和具有免疫学专长的医学肿瘤学家杰弗里·S·韦伯博士的指导下，蒙克博士将对新型HPV疗法进行两项前瞻性临床试验。首先，I3C是一种在十字花科蔬菜中发现的化合物，对HPV相关性喉乳头状瘤病有效，将在随机II期试验中评估HPV引起的生殖器疣患者的疗效。其次，计划在CIN妇女中进行编码HPV16型E7蛋白免疫原性部分的DNA质粒疫苗的I期和II期研究。蒙克博士将把他的职业生涯重点放在专门与女性下生殖道肿瘤相关的抗HPV药物领域的翻译研究上。病毒学、化学预防、免疫学和妇科肿瘤学方面的导师将使Monk博士能够在实验室和临床环境中研究独特的抗病毒药物，重点是HPV免疫。这条道路将使蒙克博士成为一名独立的研究员，能够首先在动物身上研究抗HPV疗法，然后在人类化学预防试验中进行研究。预期Monk博士将在所要求的支助期结束时获得实验室和临床研究的外部资金。

The human papillomavirus (HPV) is a significant etiologic agent in lower female genital tract neoplasia. Novel interactions with other co-carcinogens and/or immuno-deficiency lead to tumorigenesis and cancer progression. However, both the lack of adequate animal models and prospective clinical trials are impediments to the development of effective anti-HPV therapies and prevent a thorough understanding of human interactions with this virus. The objective of this proposal is to support the career development of Bradley J. Monk, M.D. Under the direction of Dr. Luis P. Villarreal, Ph.D., Dr. Monk will evaluate co-carcinogens and anti-viral agents in a recently described severe combined immunodeficiency mouse model using implanted human HPV infected epithelium, cervical intraepithelial neoplasia (CIN). Dr. Monk proposes to study the neoplastic transformation as well as the progression or regression of these cervical tissue implants. The influence of specific promoters or genotoxic compounds (e.g. hormones, nicotine) as well as novel anti-HPV agents (e.g. stimulated immune cells, anti-sense oncogenes) and nutritional supplements (e.g. indole 3-carbinol or I3C) will be studied. In addition, under the direction of Philip J. DiSaia, M.D., a Gynecologic Oncologist; Frank L. Meyskens, M.D., a Medical Oncologist with expertise in Chemoprevention; and Jeffrey S. Weber, M.D., Ph.D., a Medical Oncologist with expertise in Immunology, Dr. Monk will conduct two prospective clinical trials of novel HPV therapies. First, I3C, a compound found in cruciferous vegetables and effective in HPV related laryngeal papillomatosis, will be evaluated in patients with HPV induced genital warts in a randomized phase II trial. Second, a phase I and II study of a DNA plasmid vaccine encoding an immunogenic portion of the HPV type 16 E7 protein is planned among women with CIN. Dr. Monk will focus his career on translational research in the area of anti-HPVmodalities specifically related to female lower genital tract neoplasia. Mentors in Virology, Chemoprevention, Immunology and Gynecologic Oncology will allow Dr. Monk to investigate unique anti-viral agents both in the laboratory and in clinical settings with an emphasis on HPV immunity. This path will develop Dr. Monk into an independent investigator able to study anti-HPV therapies first in animals then in human chemoprevention trials. It is expected that Dr. Monk will have obtained extramural funding for both his laboratory and clinical studies by the end of the period of support requested.