Molecular and Theraputic Studies on HPV-associated Anal Cancer

描述(申请人提供)：肛门癌在美国和其他地方日益受到关注，特别是在艾滋病毒阳性的男性中，他们这种人类乳头瘤病毒相关肿瘤的发病率远远高于正常水平。几十年来，放化疗的标准一直保持不变，在治疗晚期或复发疾病的患者中价值有限。肛门癌是一种知之甚少的疾病，因为缺乏用于其研究的临床前模型。我们已经建立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激活，是治疗这种癌症的一个有价值的靶点。在这项拨款申请中，我们建议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化疗放射反应的影响。我们还将开展研究，进一步探讨针对mTOR和MEK/ERK通路的药物在治疗肛门癌中的价值。最后，我们将研究位于MTOR和MEK/ERK通路上游的PI3K激活是否与HPV癌基因一起驱动肛门癌的发生。这项拨款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.