Molecular and Theraputic Studies on HPV-associated Anal Cancer

描述（由申请人提供）：肛门癌在美国和其他地方越来越受到关注，特别是在HIV阳性男性中，这种人乳头瘤病毒相关肿瘤的发病率远高于正常发病率。标准化放疗几十年来一直保持不变，对晚期或复发性疾病患者的治疗价值有限。肛门癌是一种知之甚少的疾病，由于缺乏临床前模型的研究。我们开发了第一个肛门癌的临床前动物模型。利用这些模型，我们已经开始研究病毒癌基因在这种癌症中的作用。此外，我们发现mTOR通路在肛门癌中高度活化，是治疗这种癌症的有价值的靶点。在这项资助申请中，我们提出使用这些新的临床前模型进行实验，以了解单个HPV癌基因在肛门癌发生中的作用和时间要求，以及它们对肛门癌对放化疗反应的影响。我们还将开展研究，以进一步研究靶向mTOR和MEK/ERK通路的药物在治疗肛门癌中的价值。最后，我们将研究是否PI 3 K激活，这是上游的MTOR和MEK/ERK途径，驱动肛门癌与HPV癌基因。这项资助中描述的研究将为治疗人类肛门癌的更有效方法提供新的见解。

DESCRIPTION (provided by applicant): Anal cancer is of growing concern in the United States and elsewhere, particularly among HIV-positive men who have a much higher than normal incidence of this human papillomavirus-associated neoplasia. Standard of care chemoradiotherapy has remained unchanged for decades and is of limited value in treating patients with advanced or recurrent disease. Anal cancer is a poorly understood disease owing to the absence of preclinical models for its study. We have developed the first preclinical animal models for anal cancer. Using these models, we have begun to study the role of viral oncogenes in this cancer. Furthermore, we discovered that the mTOR pathway is highly activated in anal cancer and is a valuable target for treating this cancer. In this grant applicatin we propose experiments using these new preclinical models to understand the role and temporal requirements for individual HPV oncogenes in anal carcinogenesis, and their influences on the responses of anal cancer to chemoradiation. We will also carry out studies to investigate further the value of drugs targeting the mTOR and MEK/ERK pathways in treating anal cancer. Lastly we will investigate if PI3K activation, which is upstream of the MTOR and MEK/ERK pathways, drives anal carcinogenesis together with HPV oncogenes. The studies described in this grant will provide new insights into more effective ways for treating human anal cancer.