Effect of AMG 479 on anti-tumor effects of gemcitabine and erlotinib against pancreatic carcinoma xenograft models

Abstract

4617 Background: Binding of IGF-1 or IGF-2 to the type I insulin-like growth factor receptor (IGF-1R) activates intracellular signals important in the growth and survival of pancreatic tumors. AMG 479 is a fully human monoclonal antibody against IGF-1R currently in phase II clinical trials. AMG 479 exerts its anti-tumor activity by blocking ligand binding and inducing receptor downregulation in vivo. Methods: IGF-1R and Insulin Receptor (IR) levels were determined using FACS analysis or Meso Scale Detection (MSD). Level of IGF-1R and AKT phosphorylation were measured using MSD. Animal experiments were performed by injecting 5 million MiaPaCa or BxPC-3 cells subcutaneously into female athymic nude mice. Treatment began when xenografts (n=10/group) were approximately 200 mm3 and continued for the length of the experiment. AMG 479 and gemcitabine were dosed 2x/week intraperitoneally. Erlotinib was dosed orally every day. Repeated measures ANOVA was used to compare the efficacy of the treatment groups. Results: The ratios of IGF-1R to IR were 60:1 and 1.5:1 in the BxPC-3 and MiaPaCa cell lines, respectively. In vitro, AMG 479 blocked IGF-1 induced IGF-1R and AKT activation in both cell lines. In vivo, AMG 479 blocked IGF-1 induced IGF-1R activation in both cell lines but could only block AKT activation in the BxPC-3 cell line. Dose- dependent tumor growth inhibition by AMG 479 was observed in both human pancreatic carcinoma xenograft models. Maximal inhibition (70%) was achieved with a 300 μg/dose, 2x/week schedule. Analysis of tumor xenografts following AMG 479 treatment revealed significant down- regulation of IGF-1R expression (>60%). Since the survival signals driven by IGF-1R have been shown to convey resistance to traditional therapies, we tested the ability of AMG 479 to enhance the efficacy of gemcitabine or erlotinib in vivo. Both gemcitabine and erlotinib were significantly more effective in combination with AMG 479. Furthermore, the triple combination of optimal doses of AMG 479, erlotinib and gemcitabine resulted in tumor stasis and regression. Conclusions: These results demonstrate that IGF-1R blockade by AMG 479 inhibits AKT signaling and enhances the in vivo anti-tumor effects of approved therapies for the treatment of pancreatic carcinoma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Amgen