Details

Autor(en) / Beteiligte

• Gunder, Laura C.
• Moyer, Tyra H.
• Rademacher, Brooks L.
• Auyueng, Andrew S.
• Leverson, Glen
• Zhang, Wei
• Matkowskyj, Kristina A.
• Carchman, Evie H.

Titel

PI3K/mTOR inhibition prevents anal cancer in mice with established low-grade anal dysplasia

Ist Teil von

• Experimental and molecular pathology, 2022-04, Vol.125, p.104752-104752, Article 104752

Ort / Verlag

Netherlands: Elsevier Inc

Erscheinungsjahr

2022

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Low-grade anal dysplasia is a disease that can progress to high-grade anal dysplasia and eventually anal cancer if left untreated. Research has shown that low-grade anal dysplasia is marked by significant autophagic dysfunction. We hypothesized that systemic induction of autophagy, via phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibition, would be effective in preventing anal cancer development in human papillomavirus (HPV) mice (K14E6/E7) with established low-grade anal dysplasia. Mice began treatment at 15 weeks of age, when 75% of mice spontaneously develop low-grade anal dysplasia, and were divided into the following groups: no treatment, systemic LY3023414 (4.5 mg/kg, dual PI3K/mTOR inhibitor) alone, topical 7,12 dimethylbenz[a]anthracene (DMBA) alone, or systemic LY3023414 and topical DMBA. Groups were compared for final histology, PI3K activity, mTOR activity, autophagic induction (light chain 3B (LC3β)), autophagic function (p62 protein), and tumor-free survival. Untreated mice or mice treated with LY3023414 alone did not progress to cancer. There was a statistically significant decrease in the number of mice that developed histologic evidence of cancer when comparing mice that received systemic LY3203414 with topical DMBA versus those that received topical DMBA alone (p = 0.0003). PI3K and mTOR activity decreased in groups treated with systemic LY3023414 and topical DMBA as compared with those treated with topical DMBA alone (p = 0.0005 and p = 0.0271, respectively). LC3β and p62 expression was not statistically altered with systemic LY3023414 treatment. Mice developed less overt tumors and had increased tumor-free survival when treated with systemic LY3023414 in the presence of topical DMBA compared to topical DMBA alone (p = 0.0016 and p < 0.001, respectively). Systemic LY3023414 treatment is effective in anal cancer prevention in the setting of established low-grade anal dysplasia in an HPV-associated mouse model of anal cancer. •Treatment with a PI3K/mTOR inhibitor reduced the rate of anal cancer in HPV transgenic mice with low-grade anal dysplasia.•The delay in progression cancer using LY3023414 correlated with PI3K/mTOR pathway inhibition.•The delay in progression to cancer using a dual PI3K/mTOR inhibitor did not correlate with markers of autophagy.•LY3023414 increased tumor-free survival, even in the presence of the carcinogen, 7, 12 dimethylbenz[a]anthracene (DMBA).