Aspirin prolongs survival and reduces the number of Foxp3+ regulatory T cells in a genetically engineered mouse model of pancreatic cancer

Abstract

Gemcitabine became the reference regimen for advanced pancreatic cancer after a randomized trial showed significant improvement in the median overall survival. Since then, the combination of gemcitabine with a variety of cytotoxic and targeted agents has generally shown no significant survival advantage as compared with gemcitabine alone. Only the addition of erlotinib to gemcitabine resulted in a significant but very small improvement in overall survival, coming along with a very uncomfortable rash in the patients. Therefore, new adjuvant agents with very low toxic levels are needed. In this study, we used a genetically engineered mouse model of pancreatic cancer to evaluate the chemotherapeutic potential of aspirin as an adjuvant agent to gemcitabine. Drug treatment was initiated at the age of 3months. LsL-Kras (G12D) ; Pdx1-Cre or LsL-Kras (G12D) ; LsL-Trp53 (R172H) ; Pdx1-Cre transgenic mice were randomly assigned to receive either mock treatment, gemcitabine, or a combination of gemcitabine and aspirin. All mice were treated until death. The effect of aspirin was evaluated by histopathological analyses and immunostaining. Gemcitabine prolonged overall median survival of LsL-Kras (G12D) ; LsL-Trp53 (R172H) ; Pdx1-Cre mice by 31days as compared to mock-treated animals (median survival, 190 vs. 159days; p = 0.396). Addition of aspirin to gemcitabine even extended the survival for ten more days, leading to a prolonged survival by 41days, reaching virtually statistical significance versus the control group (median survival, 200 vs. 159days; p = 0.05). Furthermore, we found that administration of aspirin in combination with gemcitabine reduced the number of Foxp3(+) regulatory T cells significantly. In conclusion, we identified aspirin as an effective adjuvant agent to gemcitabine in the treatment of PDAC. While fundamental differences in biology suggest the need for caution in equating mouse tumors with their human counterparts, mouse models nevertheless represent an important source of insight regarding human neoplasia. Further studies are necessary to confirm the hypothesis that aspirin might be an effective well-tolerated chemotherapeutic adjuvant agent for pancreatic cancer.