Cetuximab is a monoclonal antibody (MoAb) against the ligand-binding domain of
the EGFR evaluated in combination with gemcitabine in a randomized phase III trial. However, the study failed to demonstrate the superiority of the combination over the gemcitabine control arm (12). Subset analysis showed that tumor EGFR expression does not predict benefit to the cetuximab-containing regimen. A phase II trial with cetuximab +/- gemcitabine and cisplatin Inhibitors,research,lifescience,medical showed medical similar negative results (13). The objective response rate was 17.5% for the combination arm versus 12.2% in control, and median progression-free and overall survivals were 4.2 months vs 3.4 months, Inhibitors,research,lifescience,medical and 7.8 months vs 7.5 months respectively. Anti-angiogenesis Pancreas cancer was thought to thrive on neovascularization and dependent on a rich blood supply as the tumors grow (14). The importance of vascular endothelial growth factor (VEGF) pathway was shown in preclinical pancreas cancer studies (15). Though the exact mechanism in patients is unclear, anti-angiogenic Inhibitors,research,lifescience,medical therapies are thought to interrupt tumor neovascularization and normalize existing inefficient tumor vasculature, thereby enhancing drug delivery and synergize the effects of cytotoxic agents. Bevacizumab, a MoAb to VEGF ligand was
studied in multiple trials. Recently published CALGB 80303 (gemcitabine +/- bevacizumab) treated 535 patients and overall response rates, Inhibitors,research,lifescience,medical median OS and PFS were 13%, 5.8 months, and 3.8 months for the gemcitabine/bevacizumab arm and 10%, 5.9 months, and 2.9 months for the gemcitabine/placebo arm, respectively (16). When bevacizumab was evaluated in combination with gemcitabine and erlotinib, the phase III trial failed to
demonstrate significant improvement by the bevacizumab-containing arm compared to control (median OS 7.1 months vs 6.2 months respectively) (8). Bevacizumab failed to improve survival when evaluated in combination with gemcitabine and capecitabine in a phase II trial (6). Despite the intial excitement, bevacizumab failed to improve Inhibitors,research,lifescience,medical survival in advanced pancreas cancer patients when evaluated in combination with standard of care. A number of small Florfenicol molecular tyrosine kinase inhibitors against VEGFR2, including sorafenib, sunitinib and vatalatinib, have being evaluated in the disease but none showed positive efficacy signal so far (6)-(9). Combination therapies targeting VEGFRs and other signaling pathways are under investigation. Insulin-like growth factor pathway The IGF axis comprises multiple circulating ligands, such as IGF-1, IGF-II and insulin, interacting with membrane bound receptors, such as type I IGF receptor (IGF-1R). The PI3k-Akt pathway is one main downstream mediator of IGF-1R signaling and plays a potentially important role in anticancer drug resistance (17).