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

Area of Science:

• Oncology
• Cancer Prevention
• Pharmacology

Background:

• Anal dysplasia and anal cancer pose significant health challenges.
• Targeting key signaling pathways like mTOR and PI3K is a potential strategy for cancer prevention.
• Understanding the efficacy of pathway inhibitors in precancerous conditions is crucial.

Purpose of the Study:

• To investigate the efficacy of mTOR and/or PI3K pathway inhibition for anal cancer prevention.
• To evaluate these inhibitors in mice with and without established anal dysplasia.
• To assess the impact of treatment timing and sex on efficacy.

Main Methods:

• K14E6/E7 mice were treated with 7,12-Dimethylbenz[a]anthracene (DMBA) to induce anal carcinoma.
• Mice received topical Pictilisib (PI3K inhibitor), Sapanisertib (mTOR inhibitor), or Samotolisib (dual PI3K/mTOR inhibitor) with or without DMBA.
• Tumor-free survival was monitored, and anal tissues were histologically analyzed for squamous cell carcinoma (SqCC).

Main Results:

• Topical Sapanisertib significantly increased tumor-free survival across different treatment start ages and sexes.
• Samotolisib, when applied topically with DMBA, decreased microscopic SqCC in male mice treated from 15 weeks of age.
• Most topical treatments with DMBA improved tumor-free survival in 15-week-old mice, with exceptions noted in males for Pictilisib.

Conclusions:

• The mTOR inhibitor Sapanisertib demonstrated broad efficacy in increasing tumor-free survival for anal cancer prevention in mice.
• The dual PI3K/mTOR inhibitor Samotolisib showed promise in reducing established microscopic anal squamous cell carcinoma in male mice.
• These findings highlight the potential of targeted pathway inhibition for anal cancer prevention strategies.