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

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.

Anal cancer; Anal dysplasia; Chemoprevention; HPV; PI3K/mTOR pathways; Squamous cell carcinoma of the anus.