Abstract C10: A novel combination of a small molecule IAP inhibitor and a TRAIL-R1 monoclonal antibody synergize to induce apoptosis in pancreatic tumor cell lines

Abstract

Abstract X-linked inhibitor of apoptosis protein (XIAP) is a critical inhibitory protein regulating the activation of apoptosis. A small molecule IAP inhibitor, HGS1029, that inhibits the anti-apoptotic activity of multiple IAPs including; XIAP, leading to tumor cell apoptosis, is currently in phase 1 trials. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) death receptors, TRAIL-R1 and TRAIL-R2, are expressed on the cell surface of many human tumor cells and activation of these receptors induces programmed cell death in a wide of variety human tumor cell lines. Mapatumumab is a fully human agonistic monoclonal antibody that targets and activates cell death via TRAIL-R1 and has demonstrated robust preclinical activity against many tumor types. Mapatumumab is currently being evaluated in phase 2 clinical trials. Because mapatumumab and HGS1029 target the apoptotic pathway at different points we hypothesized that combining two pro-apoptotic agents would have synergistic anti-tumor activity. We assessed the in vitro cytotoxic activity of mapatumumab in combination with the IAP inhibitor, HGS1029, in human pancreatic cell lines. All 8 pancreatic cell lines expressed low to moderate levels of both TRAIL-R1 and TRAIL-R2 on the cell surface. Three pancreatic cell lines were resistant (3/8) and 5 were moderately sensitive (5/8) to treatment with mapatumumab alone in an in vitro cytotoxicity assay. Four cell lines showed a very modest response to HGS1029 single agent treatment. When combined, mapatumumab and HGS1029 significantly increased cytotoxicity in these 4 weakly sensitive cell lines. Two of these cell lines were resistant to mapatumumab alone and two were sensitive. EC50 values shifted substantially in the combination treatments when compared to either agent alone. Isobologram analysis revealed this increased cytotoxicity to be synergistic in all cell lines sensitive to the combination. Investigation into the in vivo anti-tumor activity of this combination is on-going in murine xenograft models of pancreatic cancer. These results demonstrate the combination of two pro-apoptotic agents; HGS1029 and mapatumumab, that directly target and activate the apoptotic pathway, can synergize and overcome single agent resistance in pancreatic tumor cell lines. The significant anti-tumor activity of this novel combination is a potential therapeutic strategy for the treatment of human cancer. These preclinical data support the evaluation of IAP inhibitors in combination with TRAIL-R mAbs in future clinical studies. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C10.