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.