Effect of an orally active COX-2 inhibitor on the development of gallbladder carcinoma in BK5.erbB2 mice.

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Gallbladder carcinoma (GBCa) has proven challenging to treat and manage due to its poor sensitivity to conventional therapies and the inability to detect early tumor formation. We have developed transgenic mice where expression of a rat erbB2 cDNA is targeted to the basal layer of epithelial tissues by the bovine keratin 5 (BK5) promoter (BK5.erbB2 mice). Adenocarcinoma of the gallbladder develops in approximately 70% of these transgenic mice by 2 months of age. We found that the expression pattern of signal transduction molecules such as erbB2, phospho-erbB2, phospho-EGFR, Akt, COX-2 and MUC4 in GBCa in BK5.erbB2 mice was very similar to that in human biliary tract cancer (BTC). Recently, we have reported that orally active tyrosine kinase inhibitors (TKIs) were very potent therapeutic agents in this model (Kiguchi, K. et al Clin Cancer Res 11:5572–80). In this study, we examined the ability of CS-706, an orally active COX-2 inhibitor, to block the progression to GBCa in these mice. Transgenic mice bearing gallbladder tumors were identified by ultrasound imaging and received 100 ppm CS-706 dietary supplementation or control diet. Treatment began at 2 months of age and continued for 4 weeks. Tumor size was monitored weekly via ultrasound imaging. Imaging and histological analyses revealed that 78% (7 out of 9) of the mice on control diet progressed to GBCa. In contrast only 12% (4 out of 19) mice treated with CS-706 showed signs of progression. Additionally, 9 out of 19 tumors treated with CS-706 partially regressed. Future studies will address the efficacy of combination TKI and CS-706 inhibitor therapy. Based on these results, COX-2 inhibition could potentially serve as an effective adjunct therapy for GBCa.