Figure 4. Prolonged combination treatment of orthotopic mouse model with \Hh and HGF/c-Met inhibitors in combination gemcitabine leads to reduction in primary tumor volume and metastatic burden.

A. Schematic representation of two-week treatment regimen in the orthotopic mouse model of PDA. Baseline tumor volume was determined on postoperative day 5, following by weekly ultrasounds until the last day of treatment. Mice were treated daily beginning one day after the first ultrasound by oral gavage with Hh and/or HGF/c-Met inhibitors or vehicle control. Gemcitabine was administered bi-weekly via intraperitoneal injection. In the metastasis study (panel C) livers, lungs, gut and peritoneum were harvested for gross and histological analysis of metastases. B. The change in tumor volume (calculated as ratio between week 3 and baseline tumor volume) is shown. Data is representative of 1 experiment. C. Summary of total numbers of metastases formed (gross and histological) in each group. The data is representative of 1 experiment. Mice that died before the completion of the planned treatment or whose quality of tumor was not adequate for analysis due to necrosis were excluded. Gem-gemcitabine (n=7), Hh-Hh inhibitor + Gem (n=8), c-Met- HGF/c-Met inhibitor + Gem (n=10), DMSO-vehicle control (n=6), Hh+c-Met+Gem (n=8).. ns- not significant *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 (unpaired student t-test in panel B and Fisher’s exact test in panel C).