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

by Selleckchem | Jul 28 2023

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.

Comments:

Abstract: This study aimed to investigate the efficacy of inhibiting the mTOR and/or PI3K pathways in the prevention of anal cancer in mice, with or without established precancerous lesions of the anus (anal dysplasia). K14E6/E7 mice were enrolled at different ages and treated with a topical carcinogen, DMBA, to induce carcinoma development. Various treatment groups were established, including no treatment, DMBA only, and topical inhibitors of PI3K (Pictilisib), mTOR (Sapanisertib), or dual PI3K/mTOR (Samotolisib), with or without DMBA. Tumor-free survival and histological evaluation of squamous cell carcinoma (SqCC) were assessed.

The results demonstrated that all topical treatments, in combination with DMBA, increased tumor-free survival in mice starting treatment at 15 weeks of age, except for Pictilisib + DMBA in males. Sapanisertib, the mTOR inhibitor, significantly increased tumor-free survival in mice regardless of the starting age of treatment. When evaluating histological evidence of SqCC, only male mice treated with topical Samotolisib starting at 15 weeks of age exhibited a decrease in SqCC.

In conclusion, Sapanisertib, the mTOR inhibitor, showed the most pronounced effect in terms of increasing tumor-free survival, regardless of the starting time point or sex of the mice. Conversely, Samotolisib, the dual PI3K/mTOR inhibitor, reduced microscopic evidence of SqCC when initiated at 15 weeks of age but only in male mice. These findings suggest the potential of mTOR inhibition, particularly with Sapanisertib, as a preventive strategy for anal cancer, while indicating a sex-dependent response to dual PI3K/mTOR inhibition.