title: Rapamycin inhibits anal carcinogenesis in two preclinical animal models.
abstract: The incidence of anal cancer is increasing especially among HIV-infected persons in the HAART era. Treatment of this cancer is based upon traditional chemoradiotherapeutic approaches, which are associated with high morbidity and of limited effectiveness for patients with high-grade disease. The mammalian target of rapamycin (mTOR) pathway has been implicated in several human cancers, and is being investigated as a potential therapeutic target. In archival human anal cancers, we observed mTOR pathway activation. To assess response of anal cancer to mTOR inhibition, we utilized two newly developed mouse models, one in which anal cancers are induced to arise in HPV16 transgenic mice and the second a human anal cancer xenograft model. Using the transgenic mouse model, we assessed the preventative effect of rapamycin on neoplastic disease. We saw significant changes in the overall incidence of tumors, and tumor growth rate was also reduced. Using both the transgenic mouse and human anal xenograft mouse models, we studied the therapeutic effect of rapamycin on preexisting anal cancer. Rapamycin was found to significantly slow, if not stop, the growth of both mouse and human anal cancers. As has been seen in other cancers, rapamycin treatment led to an activation of the MAPK pathway. These results provide us cause to pursue further the evaluation of rapamycin as a therapeutic agent in the control of anal cancer.
authors.affiliation: McArdle Laboratory for Cancer Research, Madison, WI 53705, USA.
authors.forename: Marie K
authors.initials: MK
authors.lastname: Stelzer
authors.forename: Henry C
authors.initials: HC
authors.lastname: Pitot
authors.forename: Amy
authors.initials: A
authors.lastname: Liem
authors.forename: Denis
authors.initials: D
authors.lastname: Lee
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Kennedy
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001005:Anus Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000502:physiology; D010212:Papilloma / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D027383:Papillomaviridae / Q000235:genetics; D050725:Papillomavirus E7 Proteins / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D002273:Carcinogens; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D015127:9,10-Dimethyl-1,2-benzanthracene; D020123:Sirolimus