E. Yao1, L. Gunder1, T. Moyer1, S. Haggerty1, H. Johnson1, E. Carchman1 1University Of Wisconsin, Colorectal Surgery, Madison, WI, USA
Introduction: People living with HIV (PLWH) are at the high risk of anal dysplasia, precancerous lesion to anal cancer, advancing to anal cancer. The protease inhibitor, Saquinavir (SQV), has been shown to slow the progression of anal dysplasia to anal cancer in several preclinical mouse models of anal disease. This study aims to evaluate tumor-free survival in K14E6/E7 transgenic mice treated topically at the anus with SQV in the setting of CD4+ T-cell depletion to mimic PLWH. We hypothesize that topical SQV will effectively increase tumor-free survival in this mouse model with or without CD4+ T-cell depletion.
Methods:
K14E6/E7 mice (n=86) constitutively express oncoproteins E6 and E7 in their epithelium and spontaneously develop high-grade anal dysplasia by approximately 25 weeks of age. Mice were randomized into eight groups at 25 weeks of age: untreated or mock, 7,12-dimethylbenz[a]anthracene (DMBA) only, SQV only, SQV in combination with DMBA (SQV+DMBA) with or without CD4 depletion (100µg injections of InVivoMAb Anti-mouse CD4 (GK1.5 Antibody) every three weeks or when CD4 counts rose above 50% depletion). Mice were administered the topical carcinogen, 0.12µmol DMBA, once weekly for 20 weeks or until mice developed an overt anal tumor. DMBA was given to ensure the progression of anal dysplasia to anal tumors. A 2.5% solution of SQV was administered topically at the anus, five days a week, for the 20-week treatment period or until sacrifice. Each week, mouse anuses were thoroughly evaluated for initial tumor development and tumor growth. Survival analysis was determined by Gehan-Breslow-Wilcoxon tests using GraphPad Prism Version 9.4.1.
Results:None of the untreated or SQV-treated (SQV only) mice developed overt anal tumors during the 20-week treatment period. CD4 depleted mice treated with SQV+DMBA had significantly increased tumor-free survival as compared to the CD4 depleted Mock+DMBA-treated mice (p=0.0454). (Figure 1).
Conclusion:Topical Saquinavir, in the setting of CD4 depletion, is able to increase tumor-free survival thus, may be an effective topical therapy in PLWH to decrease the risk of progression of anal dysplasia to anal cancer.
