Topical application of a dual PI3K/mTOR inhibitor prevents anal carcinogenesis in a human papillomavirus mouse model of anal cancer
Menée à l'aide d'un modèle murin transgénique de cancer anal, cette étude montre qu'une application locale d'un composé appelé BEZ235, un inhibiteur de PI3K/mTOR, réduit la carcinogenèse anale et augmente la survie sans développement tumoral
Human papillomavirus (HPV) infection is the major risk factor for anal dysplasia that may progress to squamous cell carcinoma of the anus. We have previously shown that systemic administration of a PI3K/mTOR inhibitor (BEZ235), an autophagic inducer, results in decreased squamous cell carcinoma of the anus in our HPV mouse model. In this study, we investigate the effect of the local, topical application of a BEZ235 on tumor-free survival, histopathology, PI3K/mTOR, and autophagy. The rationale for investigating a topical formulation is the localized nature of anal dysplasia/cancer and the goal for creating a clinically translatable formulation to decrease anal carcinogenesis. In this study, HPV transgenic mice were given no treatment, topical BEZ235, topical 7,12 dimethylbenz[a]anthracene (DMBA) (carcinogen), or both topical DMBA+BEZ235. Mice were assessed for tumor development and treatment-related toxicities. Tissue was evaluated for histology, PI3K/mTOR inhibition (pS6 and pAkt), and autophagy (LC3β and p62). DMBA-alone mice had an average of 16.9 weeks tumor-free survival, whereas mice receiving both DMBA+topical BEZ235 had 19.3 weeks (P<0.000001). Histopathology revealed a significant decrease in dysplasia/carcinoma with the addition of topical BEZ235 to DMBA (P<0.000001). Comparing DMBA versus DMBA+BEZ235, topical BEZ235 resulted in a significant decrease in both pS6 and pAkt (P<0.001). Compared with no-treatment mice, both BEZ235-treated and DMBA+BEZ235-treated mice had significantly higher LC3β expression, signifying autophagic induction (P<0.01), whereas DMBA-treated, BEZ235-treated, and DMBA+BEZ235-treated mice had a significantly lower p62 expression, signifying active autophagy (P<0.0005). In conclusion, consistent with systemic delivery, topical application of BEZ235 shows decreased anal carcinogenesis through the activation of autophagy. Correspondence to Evie H. Carchman, MD, Department of Surgery, Division of Colorectal Surgery, University of Wisconsin, CSC K4/730, 600 Highland Avenue, Madison, WI 53792-7375, USA Tel: +1 608 262 0422; fax: +1 608 263 7652; e-mail: carchman@surgery.wisc.edu Received June 5, 2018 Accepted November 5, 2018 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.