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Anal Cancer Prevention Through the Topical Use of Single or Dual PI3K/mTOR Inhibitors

  • Laura C. Gunder
    Affiliations
    University of Wisconsin–Madison, School of Medicine and Public Health, Department of Surgery, 5148 Wisconsin Institute for Medical Research (WIMR), Madison, Wisconsin
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  • Author Footnotes
    1 Current address: University of Wisconsin–Madison, Waisman Center, 1500 Highland Ave, Madison, WI 53705 USA.
    Tyra H. Moyer
    Footnotes
    1 Current address: University of Wisconsin–Madison, Waisman Center, 1500 Highland Ave, Madison, WI 53705 USA.
    Affiliations
    University of Wisconsin–Madison, School of Medicine and Public Health, Department of Surgery, 5148 Wisconsin Institute for Medical Research (WIMR), Madison, Wisconsin
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  • Hillary R. Johnson
    Affiliations
    University of Wisconsin–Madison, School of Medicine and Public Health, Department of Surgery, 5148 Wisconsin Institute for Medical Research (WIMR), Madison, Wisconsin
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  • Author Footnotes
    2 Current address: Kent State University College of Podiatric Medicine, 6000 Rockside Woods Blvd N, Independence, OH 44131 USA.
    Andrew S. Auyeung
    Footnotes
    2 Current address: Kent State University College of Podiatric Medicine, 6000 Rockside Woods Blvd N, Independence, OH 44131 USA.
    Affiliations
    University of Wisconsin–Madison, School of Medicine and Public Health, Department of Surgery, 5148 Wisconsin Institute for Medical Research (WIMR), Madison, Wisconsin
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  • Glen E. Leverson
    Affiliations
    University of Wisconsin–Madison, School of Medicine and Public Health, Department of Surgery, 5148 Wisconsin Institute for Medical Research (WIMR), Madison, Wisconsin
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  • Wei Zhang
    Affiliations
    University of Wisconsin–Madison, Department of Pathology and Laboratory Medicine, 3170 UW Medical Foundation Centennial Building (MFCB), Madison, Wisconsin

    University of Wisconsin–Madison, Carbone Cancer Center, Madison, Wisconsin
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  • Kristina A. Matkowskyj
    Affiliations
    University of Wisconsin–Madison, Department of Pathology and Laboratory Medicine, 3170 UW Medical Foundation Centennial Building (MFCB), Madison, Wisconsin

    William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin

    University of Wisconsin–Madison, Carbone Cancer Center, Madison, Wisconsin
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  • Evie H. Carchman
    Correspondence
    Corresponding author. Division of Colorectal Surgery, Department of Surgery, University of Wisconsin–Madison, Clinical Science Center: 600 Highland Avenue, Madison, WI 53792-7375. Tel.: +1 608 242 2800.
    Affiliations
    University of Wisconsin–Madison, School of Medicine and Public Health, Department of Surgery, 5148 Wisconsin Institute for Medical Research (WIMR), Madison, Wisconsin

    William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin

    University of Wisconsin–Madison, Carbone Cancer Center, Madison, Wisconsin
    Search for articles by this author
  • Author Footnotes
    1 Current address: University of Wisconsin–Madison, Waisman Center, 1500 Highland Ave, Madison, WI 53705 USA.
    2 Current address: Kent State University College of Podiatric Medicine, 6000 Rockside Woods Blvd N, Independence, OH 44131 USA.
Published:October 20, 2022DOI:https://doi.org/10.1016/j.jss.2022.09.025

      Abstract

      Introduction

      Anal dysplasia and anal cancer are major health problems. This study seeks to determine if inhibition of mTOR and/or PI3K pathways is effective at anal cancer prevention in mice with/without established precancerous lesions of the anus (anal dysplasia).

      Methods

      K14E6/E7 mice were entered into the study at 5 wk, 15 wk, or 25 wk of age. Mice were treated with a topical carcinogen, 7,12-Dimethylbenz[a]anthracene (DMBA), which ensures carcinoma development within 20 wk. Treatment groups included: no treatment, DMBA only, topical Pictilisib (PI3K inhibitor) with/without DMBA, topical Sapanisertib (mTOR inhibitor) with/without DMBA, and topical Samotolisib (dual PI3K/mTOR inhibitor) with/without DMBA. Mice underwent weekly observations for anal tumor development (tumor-free survival). After 20 wk of treatment, anal tissue was harvested and evaluated histologically for squamous cell carcinoma (SqCC).

      Results

      All topical treatments in conjunction with DMBA increased tumor-free survival in mice that started treatment at 15 wk of age when compared to DMBA-only treatment, except for Pictilisib + DMBA in males. Topical Sapanisertib increased tumor-free survival in mice regardless of starting treatment age. When examining tissue for microscopic evidence of SqCC, only topical Samotolisib in males decreased SqCC in the 15 wk starting mice.

      Conclusions

      Sapanisertib, the mTOR inhibitor, had the greatest effect, in terms of increasing tumor-free survival, regardless of starting time point or sex. Unlike the other treatments, Samotolisib, the dual PI3K/mTOR inhibitor, decreased microscopic evidence of SqCC when starting treatment at 15 wk of age but only in male mice.

      Keywords

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      References

        • Deshmukh A.A.
        • Suk R.
        • Shiels M.S.
        • et al.
        Recent trends in squamous cell carcinoma of the anus incidence and mortality in the United States, 2001-2015.
        J Natl Cancer Inst. 2020; 112: 829-838
        • Johnson L.G.
        • Madeleine M.M.
        • Newcomer L.M.
        • Schwartz S.M.
        • Daling J.R.
        Anal cancer incidence and survival: the surveillance, epidemiology, and end results experience, 1973-2000.
        Cancer. 2004; 101: 281-288
        • Siegel R.L.
        • Miller K.D.
        • Fuchs H.E.
        • Jemal A.
        Cancer statistics, 2021.
        CA Cancer J Clin. 2021; 71: 7-33
        • Weis S.E.
        Current treatment options for management of anal intraepithelial neoplasia.
        Onco Targets Ther. 2013; 6: 651-665
        • Megill C.
        • Wilkin T.
        Topical therapies for the treatment of anal high-grade squamous intraepithelial lesions.
        Semin Colon Rectal Surg. 2017; 28: 86-90
        • Guo J.Y.
        • Xia B.
        • White E.
        Autophagy-mediated tumor promotion.
        Cell. 2013; 155: 1216-1219
        • Wieland U.
        • Oellig F.
        • Kreuter A.
        Anal dysplasia and anal cancer. English version.
        Hautarzt. 2020; 71: 74-81
        • Thomas M.K.
        • Pitot H.C.
        • Liem A.
        • Lambert P.F.
        Dominant role of HPV16 E7 in anal carcinogenesis.
        Virology. 2011; 421: 114-118
        • Coleman W.B.
        Chapter 4 - Neoplasia, Coleman WB, Tsongalis GJ. Essential Concepts in Molecular Pathology. 2nd ed. Academic Press, San Diego, CA2020: 55-80
        • Stelzer M.K.
        • Pitot H.C.
        • Liem A.
        • Schweizer J.
        • Mahoney C.
        • Lambert P.F.
        A mouse model for human anal cancer.
        Cancer Prev Res (Phila). 2010; 3: 1534-1541
        • Bernardi M.P.
        • Ngan S.Y.
        • Michael M.
        • et al.
        Molecular biology of anal squamous cell carcinoma: implications for future research and clinical intervention.
        Lancet Oncol. 2015; 16: e611-e621
        • Smaglo B.G.
        • Tesfaye A.
        • Halfdanarson T.R.
        • et al.
        Comprehensive multiplatform biomarker analysis of 199 anal squamous cell carcinomas.
        Oncotarget. 2015; 6: 43594-43604
        • Cacheux W.
        • Rouleau E.
        • Briaux A.
        • et al.
        Mutational analysis of anal cancers demonstrates frequent PIK3CA mutations associated with poor outcome after salvage abdominoperineal resection.
        Br J Cancer. 2016; 114: 1387-1394
        • Cacheux W.
        • Dangles-Marie V.
        • Rouleau E.
        • et al.
        Exome sequencing reveals aberrant signalling pathways as hallmark of treatment-naive anal squamous cell carcinoma.
        Oncotarget. 2017; 9: 464-476
        • Chung J.H.
        • Sanford E.
        • Johnson A.
        • et al.
        Comprehensive genomic profiling of anal squamous cell carcinoma reveals distinct genomically defined classes.
        Ann Oncol. 2016; 27: 1336-1341
        • Morris V.
        • Rao X.
        • Pickering C.
        • et al.
        Comprehensive genomic profiling of metastatic squamous cell carcinoma of the anal canal.
        Mol Cancer Res. 2017; 15: 1542-1550
        • Yang J.
        • Nie J.
        • Ma X.
        • et al.
        Targeting PI3K in cancer: mechanisms and advances in clinical trials.
        Mol Cancer. 2019; 18: 1-28
        • Shin M.K.
        • Payne S.
        • Bilger A.
        • et al.
        Activating mutations in Pik3ca contribute to anal carcinogenesis in the presence or absence of HPV-16 oncogenes.
        Clin Cancer Res. 2019; 25: 1889-1900
        • Hua H.
        • Kong Q.
        • Zhang H.
        • Wang J.
        • Luo T.
        • Jiang Y.
        Targeting mTOR for cancer therapy.
        J Hematol Oncol. 2019; 12: 1-19
        • Wang X.-W.
        Targeting mTOR network in colorectal cancer therapy.
        World J Gastroenterol. 2014; 20: 4178-4188
        • Rademacher B.L.
        • Matkowskyj K.A.
        • LaCount E.D.
        • Carchman E.H.
        Topical application of a dual PI3K/mTOR inhibitor prevents anal carcinogenesis in a human papillomavirus mouse model of anal cancer.
        Eur J Cancer Prev. 2019; 28: 483-491
        • Carchman E.H.
        • Matkowskyj K.A.
        • Meske L.
        • Lambert P.F.
        Dysregulation of autophagy contributes to.
        Anal Carcinogenesis PLoS One. 2016; 11 (e0164273): 1-21
        • Kim T.J.
        • Lee J.W.
        • Song S.
        • et al.
        Increased expression of pAKT is associated with radiation resistance in cervical cancer.
        Br J Cancer. 2006; 94: 1678-1682
        • Iida M.
        • Harari P.M.
        • Wheeler D.L.
        • Toulany M.
        Targeting AKT/PKB to improve treatment outcomes for solid tumors.
        Mutat Res. 2020; 819-820: 111690
        • Stelzer M.K.
        • Pitot H.C.
        • Liem A.
        • Lee D.
        • Kennedy G.D.
        • Lambert P.F.
        Rapamycin inhibits anal carcinogenesis in two preclinical animal models.
        Cancer Prev Res (Phila). 2010; 3: 1542-1551
        • Tian T.
        • Li X.
        • Zhang J.
        mTOR signaling in cancer and mTOR inhibitors in solid tumor targeting therapy.
        Int J Mol Sci. 2019; 20: 1-34
        • Lin C.
        • Franceschi S.
        • Clifford G.M.
        Human papillomavirus types from infection to cancer in the anus, according to sex and HIV status: a systematic review and meta-analysis.
        Lancet Infect Dis. 2018; 18: 198-206
        • Crow J.
        HPV: the global burden.
        Nature. 2012; 488: S2-S3
        • Zhang L.
        • Wu J.
        • Ling M.T.
        • Zhao L.
        • Zhao K.N.
        The role of the PI3K/Akt/mTOR signalling pathway in human cancers induced by infection with human papillomaviruses.
        Mol Cancer. 2015; 14: 1-13
        • Bossler F.
        • Kuhn B.J.
        • Günther T.
        • et al.
        Repression of human papillomavirus oncogene expression under hypoxia is mediated by PI3K/mTORC2/AKT signaling.
        mBio. 2019; 10 (e02323-18): 1-16
        • Spangle J.M.
        • Münger K.
        The human papillomavirus type 16 E6 oncoprotein activates mTORC1 signaling and increases protein synthesis.
        J Virol. 2010; 84: 9398-9407
        • Brown K.K.
        • Toker A.
        The phosphoinositide 3-kinase pathway and therapy resistance in cancer.
        F1000prime Rep. 2015; 7: 7-13
        • Surviladze Z.
        • Sterk R.T.
        • DeHaro S.A.
        • Ozbun M.A.
        Cellular entry of human papillomavirus type 16 involves activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway and inhibition of autophagy.
        J Virol. 2013; 87: 2508-2517
        • Rodrik-Outmezguine V.S.
        • Okaniwa M.
        • Yao Z.
        • et al.
        Overcoming mtor resistance mutations with a new-generation mtor inhibitor.
        Nature. 2016; 534: 272-276
        • Zunder E.R.
        • Knight Z.A.
        • Houseman B.T.
        • Apsel B.
        • Shokat K.M.
        Discovery of drug-resistant and drug-sensitizing mutations in the oncogenic PI3K isoform p110α.
        Cancer Cell. 2008; 14: 180-192
        • Wu J.
        • Chen J.
        • Zhang L.
        • Masci P.P.
        • Zhao K.N.
        Four major factors regulate phosphatidylinositol 3-kinase signaling pathway in cancers induced by infection of human papillomaviruses.
        Curr Med Chem. 2014; 21: 3057-3069
        • Porta C.
        • Paglino C.
        • Mosca A.
        Targeting PI3K/Akt/mTOR signaling in cancer.
        Front Oncol. 2014; 4: 1-11